rs144727288

Positions:

chrX-50633881-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020717.5(SHROOM4):c.2192A>G(p.Glu731Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,210,477 control chromosomes in the GnomAD database, including 6 homozygotes. There are 883 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 6 hom., 74 hem., cov: 23)

Exomes 𝑓: 0.0023 ( 0 hom. 809 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.12

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013019592).

BP6

Variant X-50633881-T-C is Benign according to our data. Variant chrX-50633881-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 197325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50633881-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5 linkuse as main transcript	c.2192A>G	p.Glu731Gly	missense_variant	4/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9 linkuse as main transcript	c.2192A>G	p.Glu731Gly	missense_variant	4/9	2	NM_020717.5	P1	Q9ULL8-1
SHROOM4	ENST00000289292.11 linkuse as main transcript	c.2192A>G	p.Glu731Gly	missense_variant	4/10	1		P1	Q9ULL8-1
SHROOM4	ENST00000460112.3 linkuse as main transcript	c.1844A>G	p.Glu615Gly	missense_variant	3/8	5			Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

245

AN:

112316

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

AN XY:

34480

show subpopulations

Gnomad AFR

AF:

0.000421

Gnomad AMI

AF:

0.0791

Gnomad AMR

AF:

0.000281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00258

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00197

GnomAD3 exomes

AF:

0.00136

AC:

249

AN:

183079

Hom.:

AF XY:

0.00130

AC XY:

AN XY:

67567

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00331

Gnomad NFE exome

AF:

0.00218

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00227

AC:

2490

AN:

1098161

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

809

AN XY:

363515

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00284

Gnomad4 NFE exome

AF:

0.00273

Gnomad4 OTH exome

AF:

0.00119

GnomAD4 genome

AF:

0.00218

AC:

245

AN:

112316

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

AN XY:

34480

show subpopulations

Gnomad4 AFR

AF:

0.000421

Gnomad4 AMR

AF:

0.000281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00258

Gnomad4 NFE

AF:

0.00293

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.00240

Hom.:

104

Bravo

AF:

0.00223

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00588

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00238

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.00267

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2016	This alteration is classified as likely 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2019	Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

X-linked intellectual disability, Stocco dos Santos type

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.0089

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.78

T;.;T

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.3

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.4

D;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0080

D;D;T

Polyphen

1.0

D;D;.

Vest4

0.45

MVP

0.98

MPC

0.57

ClinPred

0.034

GERP RS

5.7

Varity_R

0.63

gMVP

0.49

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