chrX-50607728-T-C

Variant names:

• chrX-50607728-T-C
• rs6614552
• NM_020717.5:c.3414A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020717.5(SHROOM4):​c.3414A>G​(p.Glu1138Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,112,932 control chromosomes in the GnomAD database, including 1,063 homozygotes. There are 2,868 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (609 hom., 1315 hem., cov: 19)
  • Exomes 𝑓: 0.0078 (454 hom. 1553 hem.)
• Consequence: SHROOM4 NM_020717.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.38

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BP6: Variant X-50607728-T-C is Benign according to our data. Variant chrX-50607728-T-C is described in ClinVar as [Benign]. Clinvar id is 95972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.3414A>G	p.Glu1138Glu	synonymous_variant	Exon 6 of 9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.3414A>G	p.Glu1138Glu	synonymous_variant	Exon 6 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.3414A>G	p.Glu1138Glu	synonymous_variant	Exon 6 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.3066A>G	p.Glu1022Glu	synonymous_variant	Exon 5 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 6724 AN: 105625 Hom.: 605 Cov.: 19 AF XY: 0.0453 AC XY: 1298 AN XY: 28685

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000884

Gnomad FIN AF: 0.000184

Gnomad MID AF: 0.0217

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.0494

GnomAD3 exomes AF: 0.0189 AC: 2404 AN: 127114 Hom.: 165 AF XY: 0.0125 AC XY: 408 AN XY: 32658

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.000186

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.000829

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.00777 AC: 7827 AN: 1007271 Hom.: 454 Cov.: 27 AF XY: 0.00514 AC XY: 1553 AN XY: 302339

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.000545

Gnomad4 NFE exome AF: 0.000990

Gnomad4 OTH exome AF: 0.0196

GnomAD4 genome AF: 0.0639 AC: 6753 AN: 105661 Hom.: 609 Cov.: 19 AF XY: 0.0458 AC XY: 1315 AN XY: 28733

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000887

Gnomad4 FIN AF: 0.000184

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0635 Hom.: 257

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 12, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 25, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SHROOM4-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.25
DANN	Benign	0.42

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

LitVar

Other links and lift over

dbSNP: rs6614552; hg19: chrX-50350728; COSMIC: COSV56788368;