SRRM4

Chr 12

serine/arginine repetitive matrix 4

Also known as: KIAA1853, MU-MB-2.76, nSR100

NCBI Gene: 84530 ENSG00000139767 UniProt: A7MD48 OMIM: 613103

The protein functions as a splicing factor that promotes neural-specific exon inclusion and is specifically required for neural cell differentiation. Mutations cause neurodevelopmental disorders with intellectual disability, developmental delay, and seizures, with some patients showing autism spectrum disorder features. The gene follows autosomal recessive inheritance and is highly constrained against loss-of-function mutations.

OMIM ResearchSummary from RefSeq, UniProt

SRRM4 promotes alternative splicing and inclusion of neural-specific exons in target mRNAs (Calarco et al., 2009 [PubMed 19737518]).[supplied by OMIM, Oct 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.41

Clinical Summary— SRRM4

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

92 VUS of 101 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.465

Z-score 4.10

OE 0.22 (0.12–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.39Z-score

OE missense 0.80 (0.73–0.88)

311 obs / 388.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.12–0.41)

0≤0.351.4

Missense OE?0.80 (0.73–0.88)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 7 / 32.0Missense obs/exp: 311 / 388.2Syn Z: 0.21

This gene — mechanism propensity

0.5181th %ile

GOF

0.4874th %ile

LOF

0.66top 25%

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

LOFprediction above median · LOEUF 0.41

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

ClinVar Variant Classifications

101 submitted variants in ClinVar

ClinVar

Classification Summary

VUS92

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	1	91	92
Likely Benign	0	4	4
Benign	0	0	0
Total	1	95	96

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap SRRM4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →