AFF3

Chr 2AD

ALF transcription elongation factor 3

Also known as: KINS, LAF4, MLLT2-like

NCBI Gene: 3899 ENSG00000144218 UniProt: P51826 OMIM: 601464

AFF3 encodes a nuclear transcriptional activator that binds double-stranded DNA and functions in lymphoid development. Mutations cause KINSSHIP syndrome, an autosomal dominant disorder. This gene is highly constrained against loss-of-function mutations (pLI = 1.0, LOEUF = 0.22), indicating intolerance to protein-truncating variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.221 OMIM phenotype

Clinical Summary— AFF3

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.71Z-score

OE missense 0.82 (0.77–0.88)

607 obs / 737.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.07–0.22)

0≤0.351.4

Missense OE?0.82 (0.77–0.88)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 7 / 59.4Missense obs/exp: 607 / 737.9Syn Z: 0.23

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongAFF3-related KINSSHIP syndromeOTHERAD

moderateAFF3-related intellectual disabilityOTHERAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.2597th %ile

LOF

0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.22

Literature Evidence

LOFHaploinsufficiency for LAF4/AFF3 is associated with limb, brain and urogenital malformations and specific changes of the tibia that are part of the NS spectrum.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References