X-50598412-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020717.5(SHROOM4):c.4066G>A(p.Val1356Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,207,779 control chromosomes in the GnomAD database, including 5 homozygotes. There are 279 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., 36 hem., cov: 22)

Exomes 𝑓: 0.00081 ( 4 hom. 243 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.292

Variant links:

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]

SHROOM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037336648).

BP6

Variant X-50598412-C-T is Benign according to our data. Variant chrX-50598412-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50598412-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000815 (893/1096138) while in subpopulation AMR AF= 0.0194 (680/34995). AF 95% confidence interval is 0.0182. There are 4 homozygotes in gnomad4_exome. There are 243 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.4066G>A	p.Val1356Ile	missense_variant	Exon 8 of 9	ENST00000376020.9	NP_065768.2	Q9ULL8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHROOM4	ENST00000376020.9 link	c.4066G>A	p.Val1356Ile	missense_variant	Exon 8 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.4066G>A	p.Val1356Ile	missense_variant	Exon 8 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.3718G>A	p.Val1240Ile	missense_variant	Exon 7 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

130

AN:

111589

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

33767

show subpopulations

Gnomad AFR

AF:

0.000359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00944

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00337

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00266

GnomAD3 exomes

AF:

0.00319

AC:

565

AN:

177184

Hom.:

AF XY:

0.00217

AC XY:

135

AN XY:

62098

show subpopulations

Gnomad AFR exome

AF:

0.000393

Gnomad AMR exome

AF:

0.0188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00259

Gnomad SAS exome

AF:

0.000277

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000254

Gnomad OTH exome

AF:

0.00227

GnomAD4 exome

AF:

0.000815

AC:

893

AN:

1096138

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

243

AN XY:

361634

show subpopulations

Gnomad4 AFR exome

AF:

0.000303

Gnomad4 AMR exome

AF:

0.0194

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00465

Gnomad4 SAS exome

AF:

0.000205

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.000826

GnomAD4 genome

AF:

0.00116

AC:

129

AN:

111641

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

33829

show subpopulations

Gnomad4 AFR

AF:

0.000358

Gnomad4 AMR

AF:

0.00934

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00338

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00263

Alfa

AF:

0.000467

Hom.:

Bravo

AF:

0.00189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00227

AC:

275

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Feb 09, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2018

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. -

SHROOM4-related disorder

Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.4

DANN

Benign

0.69

DEOGEN2

Benign

0.0064

T;T;.

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.43

T;.;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.010

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.015

B;B;.

Vest4

0.064

MVP

0.12

MPC

0.087

ClinPred

0.0038

GERP RS

0.65

Varity_R

0.042

gMVP

0.089

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over