X-50598352-C-T

Variant names:

• chrX-50598352-C-T
• NM_020717.5:c.4126G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020717.5(SHROOM4):​c.4126G>A​(p.Val1376Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,986 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

Genes affected

SHROOM4 (HGNC:29215): (shroom family member 4) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38578424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.4126G>A	p.Val1376Ile	missense_variant	Exon 8 of 9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4126G>A	p.Val1376Ile	missense_variant	Exon 8 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.4126G>A	p.Val1376Ile	missense_variant	Exon 8 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.3778G>A	p.Val1260Ile	missense_variant	Exon 7 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097986 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363348

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4126G>A (p.V1376I) alteration is located in exon 8 (coding exon 8) of the SHROOM4 gene. This alteration results from a G to A substitution at nucleotide position 4126, causing the valine (V) at amino acid position 1376 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.43
MutPred		0.55		Gain of ubiquitination at K1374 (P = 0.0872);Gain of ubiquitination at K1374 (P = 0.0872);.;
MVP		0.36
MPC		0.48
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-50341352;