chrX-50596930-C-A

Position:

• chrX-50596930-C-A

Variant summary

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

The NM_020717.5(SHROOM4):​c.4247G>T​(p.Gly1416Val) 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. 12/20 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: 0.578

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=0.28000712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.4247G>T	p.Gly1416Val	missense_variant	9/9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4247G>T	p.Gly1416Val	missense_variant	9/9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.4247G>T	p.Gly1416Val	missense_variant	9/10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.3899G>T	p.Gly1300Val	missense_variant	8/8	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.4247G>T (p.G1416V) alteration is located in exon 9 (coding exon 9) of the SHROOM4 gene. This alteration results from a G to T substitution at nucleotide position 4247, causing the glycine (G) at amino acid position 1416 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T;T;.
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.79	T;.;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.12
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.27	T;T;D
Polyphen		0.41	B;B;.
Vest4		0.32
MutPred		0.42		Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);.;
MVP		0.17
MPC		0.53
ClinPred		0.78	D
GERP RS		3.9
Varity_R		0.24
gMVP		0.095

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-50339930;