rs189694750

Positions:

chrX-50635637-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020717.5(SHROOM4):c.436C>T(p.Arg146Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,206,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 93 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 11 hem., cov: 21)

Exomes 𝑓: 0.00019 ( 0 hom. 82 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.91

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:

SHROOM4 (HGNC:):

SHROOM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058234334).

BP6

Variant X-50635637-G-A is Benign according to our data. Variant chrX-50635637-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-50635637-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5 linkuse as main transcript	c.436C>T	p.Arg146Trp	missense_variant	4/9	ENST00000376020.9	NP_065768.2	Q9ULL8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SHROOM4	ENST00000376020.9 linkuse as main transcript	c.436C>T	p.Arg146Trp	missense_variant	4/9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 linkuse as main transcript	c.436C>T	p.Arg146Trp	missense_variant	4/10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 linkuse as main transcript	c.88C>T	p.Arg30Trp	missense_variant	3/8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

109439

Hom.:

Cov.:

AF XY:

0.000346

AC XY:

AN XY:

31747

show subpopulations

Gnomad AFR

AF:

0.0000334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00723

Gnomad SAS

AF:

0.00127

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0000572

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000680

AC:

124

AN:

182456

Hom.:

AF XY:

0.000746

AC XY:

AN XY:

67020

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00759

Gnomad SAS exome

AF:

0.000372

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000982

Gnomad OTH exome

AF:

0.000887

GnomAD4 exome

AF:

0.000188

AC:

206

AN:

1097314

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

AN XY:

362966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00424

Gnomad4 SAS exome

AF:

0.000426

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000439

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.000301

AC:

AN:

109489

Hom.:

Cov.:

AF XY:

0.000346

AC XY:

AN XY:

31807

show subpopulations

Gnomad4 AFR

AF:

0.0000333

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00725

Gnomad4 SAS

AF:

0.00127

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000572

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000514

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked intellectual disability, Stocco dos Santos type

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Nov 15, 2022	- -

SHROOM4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2020

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

T;T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.29

MVP

0.76

MPC

0.47

ClinPred

0.076

GERP RS

6.1

Varity_R

0.65

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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