X-50596867-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020717.5(SHROOM4):c.4310G>A(p.Gly1437Asp) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.264

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02736929).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5	c.4310G>A	p.Gly1437Asp	missense_variant	9/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4310G>A	p.Gly1437Asp	missense_variant	9/9	2	NM_020717.5	P1
SHROOM4	ENST00000289292.11	c.4310G>A	p.Gly1437Asp	missense_variant	9/10	1		P1
SHROOM4	ENST00000460112.3	c.3962G>A	p.Gly1321Asp	missense_variant	8/8	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.4310G>A (p.G1437D) alteration is located in exon 9 (coding exon 9) of the SHROOM4 gene. This alteration results from a G to A substitution at nucleotide position 4310, causing the glycine (G) at amino acid position 1437 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	14
Dann	Benign	0.75
DEOGEN2	Benign	0.0023	T;T;.
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.66	T;.;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.28	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.7	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.11
MVP		0.16
MPC		0.15
ClinPred		0.12	T
GERP RS		2.2
Varity_R		0.089
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1929137928; hg19: chrX-50339867; COSMIC: COSV56795393; COSMIC: COSV56795393;