SHROOM4

Chr X

shroom family member 4

Also known as: MRXSSDS, SHAP, shrm4

NCBI Gene: 57477 ENSG00000158352 UniProt: Q9ULL8 OMIM: 300579

The protein regulates cytoskeletal architecture by modulating the spatial distribution of myosin II and plays an important role in development. Mutations cause X-linked Stocco dos Santos syndrome, characterized by cognitive disabilities. This gene is highly constrained against loss-of-function variants (pLI = 1.0), indicating that functional copies are essential for normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the APX/Shroom family, which contain an N-terminal PDZ domain and a C-terminal ASD2 motif. The encoded protein may play a role in cytoskeletal architecture. Mutations in this gene have been linked to the X-linked Stocco dos Santos syndrome characterized by cognitive disabilities. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.23

Clinical Summary— SHROOM4

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDisputed

Disputed — evidence questions this relationship

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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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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 231 VUS of 402 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 5.31

OE 0.10 (0.05–0.23)

Highly constrained

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

Missense Constraint?

0.95Z-score

OE missense 0.89 (0.82–0.95)

502 obs / 565.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.23)

0≤0.351.4

Missense OE?0.89 (0.82–0.95)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 4 / 40.5Missense obs/exp: 502 / 565.7Syn Z: 0.33

This gene — mechanism propensity

0.4190th %ile

GOF

0.3491th %ile

LOF

0.70top 10%

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

LOFprediction above median · LOEUF 0.23

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

402 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS231

Likely Benign47

Benign16

Conflicting8

Likely Pathogenic

231

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	5	220	2	4	231
Likely Benign	0	26	2	19	47
Benign	0	13	1	2	16
Conflicting	—				8
Total	6	259	5	25	303

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

View in ClinVar →

86 pathogenic / likely-pathogenic (of 98) ClinVar copy-number / structural variants overlap SHROOM4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →