GRAP

Chr 17AR

GRB2 related adaptor protein

Also known as: DFNB114

NCBI Gene: 10750 ENSG00000154016 UniProt: Q13588 OMIM: 604330

This gene encodes a cytoplasmic signaling protein that couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway through its SH2 and SH3 domains. Mutations cause autosomal recessive deafness-114, affecting inner ear function and hearing. The gene shows tolerance to loss-of-function variants (pLI = 0.11), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the GRB2/Sem5/Drk family and functions as a cytoplasmic signaling protein which contains an SH2 domain flanked by two SH3 domains. The SH2 domain interacts with ligand-activated receptors for stem cell factor and erythropoietin, and facilitates the formation of a stable complex with the BCR-ABL oncoprotein. This protein also associates with the Ras guanine nucleotide exchange factor SOS1 (son of sevenless homolog 1) through its N-terminal SH3 domain. In general, it couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. [provided by RefSeq, Jul 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.221 OMIM phenotype

Clinical Summary— GRAP

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.11) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.22LOEUF

pLI 0.111

Z-score 1.28

OE 0.39 (0.16–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.14Z-score

OE missense 0.64 (0.50–0.81)

49 obs / 77.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.16–1.22)

0≤0.351.4

Missense OE?0.64 (0.50–0.81)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 2 / 5.1Missense obs/exp: 49 / 77.1Syn Z: 0.50

This gene — mechanism propensity

0.6939th %ile

GOF

0.72top 25%

LOF

0.2872th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.