X-50598369-C-T

Variant names:

• chrX-50598369-C-T
• NM_020717.5:c.4109G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020717.5(SHROOM4):​c.4109G>A​(p.Gly1370Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.4109G>A	p.Gly1370Glu	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.4109G>A	p.Gly1370Glu	missense_variant	Exon 8 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.4109G>A	p.Gly1370Glu	missense_variant	Exon 8 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.3761G>A	p.Gly1254Glu	missense_variant	Exon 7 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4109G>A (p.G1370E) 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 4109, causing the glycine (G) at amino acid position 1370 to be replaced by a glutamic acid (E). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.035	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.72
MutPred		0.67		Loss of ubiquitination at K1374 (P = 0.0787);Loss of ubiquitination at K1374 (P = 0.0787);.;
MVP		0.42
MPC		0.60
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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-50341369;