AFF3

Chr 2AD

ALF transcription elongation factor 3

Also known as: KINS, LAF4, MLLT2-like

NCBI Gene: 3899ENSG00000144218UniProt: P51826

This gene encodes a tissue-restricted nuclear transcriptional activator that is preferentially expressed in lymphoid tissue. Isolation of this protein initially defined a highly conserved LAF4/MLLT2 gene family of nuclear transcription factors that may function in lymphoid development and oncogenesis. In some ALL patients, this gene has been found fused to the gene for MLL. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

KINSSHIP syndromeMIM #619297
AD
318
ClinVar variants
28
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— AFF3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 219 VUS of 318 total submissions
Some data sources returned errors (1)

opentargets: Error: Internal server error

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.22LOEUF
pLI 1.000
Z-score 6.30
OE 0.12 (0.07–0.22)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.71Z-score
OE missense 0.82 (0.77–0.88)
607 obs / 737.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.07–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.77–0.88)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 7 / 59.4Missense obs/exp: 607 / 737.9Syn Z: 0.23

ClinVar Variant Classifications

318 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic10
VUS219
Likely Benign50
Benign15
Conflicting6
18
Pathogenic
10
Likely Pathogenic
219
VUS
50
Likely Benign
15
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
6
12
0
18
Likely Pathogenic
3
3
4
0
10
VUS
6
189
23
1
219
Likely Benign
0
12
6
32
50
Benign
2
2
3
8
15
Conflicting
—6
Total112124841318

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

AFF3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AFF3-related KINSSHIP syndrome

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

AFF3-related intellectual disability

moderate
ADUndeterminedDecreased Gene Product Level
Dev. Disorders
G2P ↗
frameshift variant NMD triggeringcopy number variation

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

KINSSHIP syndrome

MIM #619297

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.
Bassani S et al.·Genome Med
2024Functional
A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability.
Jadhav B et al.·Nat Genet
2024
Loss of AR-regulated AFF3 contributes to prostate cancer progression and reduces ferroptosis sensitivity by downregulating ACSL4 based on single-cell sequencing analysis.
Fan A et al.·Apoptosis
2024
A novel variant in AFF3 underlying isolated syndactyly.
Khan H et al.·Clin Genet
2023
AFF3 upregulation mediates tamoxifen resistance in breast cancers.
Shi Y et al.·J Exp Clin Cancer Res
2018
Association of AFF1 rs340630 and AFF3 rs10865035 polymorphisms with systemic lupus erythematosus in a Chinese population.
Cen H et al.·Immunogenetics
2012
A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort.
Fazal S et al.·Genet Med
2025Cohort
De novo AFF3 variant in a patient with mesomelic dysplasia with foot malformation.
Shimizu D et al.·J Hum Genet
2019Case report
Genome-wide linkage and positional association analyses identify associations of novel AFF3 and NTM genes with triglycerides: the GenSalt study.
Li C et al.·J Genet Genomics
2015
A complex KMT2A::AFF3 fusion resulting from a three-way chromosomal rearrangement in pediatric B lymphoblastic leukemia.
Miller LJ et al.·Cancer Genet
2022Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools