rs142189648

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020717.5(SHROOM4):c.731A>G(p.Asn244Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,200,910 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 103 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00031 ( 0 hom. 95 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.87

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

X-linked intellectual disability, Stocco dos Santos type
Inheritance: XL Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
complex neurodevelopmental disorder
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

SHROOM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068139136).

BP6

Variant X-50635342-T-C is Benign according to our data. Variant chrX-50635342-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 212182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.731A>G	p.Asn244Ser	missense_variant	Exon 4 of 9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SHROOM4	ENST00000376020.9 link	c.731A>G	p.Asn244Ser	missense_variant	Exon 4 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11 link	c.731A>G	p.Asn244Ser	missense_variant	Exon 4 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3 link	c.383A>G	p.Asn128Ser	missense_variant	Exon 3 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes

AF:

0.000259

AC:

AN:

111810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00313

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000268

AC:

AN:

160256

AF XY:

0.000139

show subpopulations

Gnomad AFR exome

AF:

0.000267

Gnomad AMR exome

AF:

0.000935

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000869

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000314

AC:

342

AN:

1089051

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

356303

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26261

American (AMR)

AF:

0.000818

AC:

AN:

34233

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19178

East Asian (EAS)

AF:

0.00838

AC:

250

AN:

29842

South Asian (SAS)

AF:

0.0000190

AC:

AN:

52571

European-Finnish (FIN)

AF:

0.0000252

AC:

AN:

39720

Middle Eastern (MID)

AF:

0.000729

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.0000478

AC:

AN:

837431

Other (OTH)

AF:

0.000306

AC:

AN:

45697

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000259

AC:

AN:

111859

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

34065

show subpopulations

African (AFR)

AF:

0.000259

AC:

AN:

30852

American (AMR)

AF:

0.000470

AC:

AN:

10630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00313

AC:

AN:

3509

South Asian (SAS)

AF:

0.00

AC:

AN:

2603

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6142

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000754

AC:

AN:

53057

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000190

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 26, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.96

BayesDel_noAF

Benign

-1.2

CADD

Benign

0.0010

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.0020

T;T;.

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.20

T;.;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.060

N;N;.

PhyloP100

-3.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.14

N;N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.87

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.015

MVP

0.12

MPC

0.082

ClinPred

0.0036

GERP RS

-10

Varity_R

0.019

gMVP

0.074

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over