rs148911180

Positions:

chrX-50695789-C-T

Variant summary

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

The NM_020717.5(SHROOM4):c.266G>A(p.Arg89Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,210,207 control chromosomes in the GnomAD database, including 6 homozygotes. There are 755 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., 38 hem., cov: 23)

Exomes 𝑓: 0.0016 ( 5 hom. 717 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.57

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=0.009545982).

BP6

Variant X-50695789-C-T is Benign according to our data. Variant chrX-50695789-C-T is described in ClinVar as [Benign]. Clinvar id is 212178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50695789-C-T is described in Lovd as [Benign]. Variant chrX-50695789-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00163 (1790/1098117) while in subpopulation MID AF= 0.0237 (98/4136). AF 95% confidence interval is 0.0199. There are 5 homozygotes in gnomad4_exome. There are 717 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 38 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5 linkuse as main transcript	c.266G>A	p.Arg89Lys	missense_variant	2/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9 linkuse as main transcript	c.266G>A	p.Arg89Lys	missense_variant	2/9	2	NM_020717.5	P1	Q9ULL8-1
SHROOM4	ENST00000289292.11 linkuse as main transcript	c.266G>A	p.Arg89Lys	missense_variant	2/10	1		P1	Q9ULL8-1
SHROOM4	ENST00000484922.1 linkuse as main transcript	n.149G>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

136

AN:

112033

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

34195

show subpopulations

Gnomad AFR

AF:

0.000292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.0106

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00463

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0130

Gnomad NFE

AF:

0.000977

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00213

AC:

391

AN:

183143

Hom.:

AF XY:

0.00256

AC XY:

173

AN XY:

67675

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00744

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.00464

GnomAD4 exome

AF:

0.00163

AC:

1790

AN:

1098117

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

717

AN XY:

363493

show subpopulations

Gnomad4 AFR exome

AF:

0.000417

Gnomad4 AMR exome

AF:

0.00185

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00761

Gnomad4 FIN exome

AF:

0.0000740

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.00317

GnomAD4 genome

AF:

0.00120

AC:

135

AN:

112090

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

34262

show subpopulations

Gnomad4 AFR

AF:

0.000292

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.0106

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.00465

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000977

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00208

AC:

ExAC

AF:

0.00230

AC:

279

EpiCase

AF:

0.00256

EpiControl

AF:

0.00231

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 10, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2015	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0067

T;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

T;.

M_CAP

Benign

0.022

MetaRNN

Benign

0.0095

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.25

Sift

Benign

0.13

T;T

Sift4G

Benign

0.48

T;T

Polyphen

1.0

D;D

Vest4

0.13

MVP

0.19

MPC

0.42

ClinPred

0.025

GERP RS

5.2

Varity_R

0.13

gMVP

0.84

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