X-50596701-A-C

Variant names:

• chrX-50596701-A-C
• NM_020717.5:c.4476T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020717.5(SHROOM4):​c.4476T>G​(p.Asn1492Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.494

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13704309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.4476T>G	p.Asn1492Lys	missense_variant	Exon 9 of 9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4476T>G	p.Asn1492Lys	missense_variant	Exon 9 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.4476T>G	p.Asn1492Lys	missense_variant	Exon 9 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.4128T>G	p.Asn1376Lys	missense_variant	Exon 8 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4476T>G (p.N1492K) alteration is located in exon 9 (coding exon 9) of the SHROOM4 gene. This alteration results from a T to G substitution at nucleotide position 4476, causing the asparagine (N) at amino acid position 1492 to be replaced by a lysine (K). 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0077	T;T;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.22	N;N;N
REVEL	Benign	0.078
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.17
MutPred		0.18		Gain of methylation at N1492 (P = 0.0067);Gain of methylation at N1492 (P = 0.0067);.;
MVP		0.28
MPC		0.56
ClinPred		0.83	D
GERP RS		3.3
Varity_R		0.22
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-50339701;