rs148721221

Positions:

chrX-50607531-T-C

Variant summary

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

The NM_020717.5(SHROOM4):c.3611A>G(p.Glu1204Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,209,350 control chromosomes in the GnomAD database, including 19 homozygotes. There are 541 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., 55 hem., cov: 21)

Exomes 𝑓: 0.0014 ( 17 hom. 486 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.67

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004429966).

BP6

Variant X-50607531-T-C is Benign according to our data. Variant chrX-50607531-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130310.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chrX-50607531-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.3611A>G	p.Glu1204Gly	missense_variant	6/9	ENST00000376020.9	NP_065768.2	Q9ULL8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SHROOM4	ENST00000376020.9 link	c.3611A>G	p.Glu1204Gly	missense_variant	6/9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.3611A>G	p.Glu1204Gly	missense_variant	6/10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.3263A>G	p.Glu1088Gly	missense_variant	5/8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

186

AN:

111044

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

AN XY:

33262

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000955

Gnomad ASJ

AF:

0.0479

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00427

Gnomad NFE

AF:

0.000755

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00251

AC:

461

AN:

183465

Hom.:

AF XY:

0.00200

AC XY:

136

AN XY:

67901

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.000510

Gnomad ASJ exome

AF:

0.0466

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000916

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00145

AC:

1590

AN:

1098253

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

486

AN XY:

363609

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.000483

Gnomad4 ASJ exome

AF:

0.0479

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000511

Gnomad4 OTH exome

AF:

0.00417

GnomAD4 genome

AF:

0.00167

AC:

186

AN:

111097

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

AN XY:

33325

show subpopulations

Gnomad4 AFR

AF:

0.000131

Gnomad4 AMR

AF:

0.000954

Gnomad4 ASJ

AF:

0.0479

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000755

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00308

Hom.:

145

Bravo

AF:

0.00169

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00198

AC:

241

EpiCase

AF:

0.00158

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 11, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0085

T;T;.

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.67

T;.;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.047

Sift

Uncertain

0.0010

D;D;D

Sift4G

Benign

0.077

T;T;D

Polyphen

0.010

B;B;.

Vest4

0.10

MVP

0.082

MPC

0.47

ClinPred

0.042

GERP RS

3.2

Varity_R

0.14

gMVP

0.44

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