chrX-50634194-G-A

Position:

chrX-50634194-G-A

Variant summary

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

The NM_020717.5(SHROOM4):c.1879C>T(p.Pro627Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,209,641 control chromosomes in the GnomAD database, including 5 homozygotes. There are 912 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., 46 hem., cov: 23)

Exomes 𝑓: 0.0025 ( 5 hom. 866 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.523

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007726848).

BP6

Variant X-50634194-G-A is Benign according to our data. Variant chrX-50634194-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50634194-G-A is described in Lovd as [Benign]. Variant chrX-50634194-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 46 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5 linkuse as main transcript	c.1879C>T	p.Pro627Ser	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.1879C>T	p.Pro627Ser	missense_variant	4/9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 linkuse as main transcript	c.1879C>T	p.Pro627Ser	missense_variant	4/10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 linkuse as main transcript	c.1531C>T	p.Pro511Ser	missense_variant	3/8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

163

AN:

111517

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

AN XY:

33701

show subpopulations

Gnomad AFR

AF:

0.000294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.000379

Gnomad FIN

AF:

0.000330

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00283

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00142

AC:

261

AN:

183309

Hom.:

AF XY:

0.00145

AC XY:

AN XY:

67773

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.00285

Gnomad OTH exome

AF:

0.000884

GnomAD4 exome

AF:

0.00245

AC:

2693

AN:

1098075

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

866

AN XY:

363451

show subpopulations

Gnomad4 AFR exome

AF:

0.000417

Gnomad4 AMR exome

AF:

0.000312

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000425

Gnomad4 FIN exome

AF:

0.000518

Gnomad4 NFE exome

AF:

0.00299

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00146

AC:

163

AN:

111566

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

AN XY:

33760

show subpopulations

Gnomad4 AFR

AF:

0.000293

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000284

Gnomad4 SAS

AF:

0.000381

Gnomad4 FIN

AF:

0.000330

Gnomad4 NFE

AF:

0.00283

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00275

Hom.:

107

Bravo

AF:

0.00130

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00297

AC:

ExAC

AF:

0.00118

AC:

143

EpiCase

AF:

0.00267

EpiControl

AF:

0.00207

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 02, 2014	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2012

In silico models in agreement (benign);Insufficient or conflicting evidence -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.0053

T;T;.

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.76

T;.;T

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.0077

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.0

L;L;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.011

D;D;D

Sift4G

Benign

0.75

T;T;T

Polyphen

0.0080

B;B;.

Vest4

0.026

MVP

0.58

MPC

0.23

ClinPred

0.0069

GERP RS

4.2

Varity_R

0.085

gMVP

0.17

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