AFF2

Chr X

ALF transcription elongation factor 2

Also known as: FMR2, FMR2P, FRAXE, MRX2, OX19, XLID109

NCBI Gene: 2334 ENSG00000155966 UniProt: P51816

This RNA-binding protein is involved in alternative splicing regulation and is highly constrained against loss-of-function variants (pLI 0.996, LOEUF 0.275). Mutations cause X-linked intellectual developmental disorder 109 (Fragile X E syndrome), a form of nonsyndromic cognitive disability resulting from expansion of GCC repeats in the gene that leads to gene silencing. The condition follows X-linked recessive inheritance.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a putative transcriptional activator that is a member of the AF4\FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked cognitive disability. In addition, this gene contains 6-25 GCC repeats that are expanded to >200 repeats in the disease state. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jul 2016]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.28

Clinical Summary— AFF2

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Gene-Disease Validity (ClinGen)

non-syndromic X-linked intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.996

Z-score 4.98

OE 0.13 (0.07–0.28)

Highly constrained

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

Missense Constraint?

1.41Z-score

OE missense 0.82 (0.76–0.89)

413 obs / 502.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.28)

0≤0.351.4

Missense OE?0.82 (0.76–0.89)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 5 / 38.2Missense obs/exp: 413 / 502.0Syn Z: -1.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveAFF2-related fragile X-E intellectual developmental disorderOTHERXLR

This gene — mechanism propensity

0.2997th %ile

GOF

0.2796th %ile

LOF

0.83top 5%

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

LOFprediction above median · LOEUF 0.28 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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