rs189694750

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020717.5(SHROOM4):c.436C>T(p.Arg146Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,206,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 93 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 11 hem., cov: 21)

Exomes 𝑓: 0.00019 ( 0 hom. 82 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.91

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058234334).

BP6

Variant X-50635637-G-A is Benign according to our data. Variant chrX-50635637-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 417739.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.436C>T	p.Arg146Trp	missense_variant	Exon 4 of 9	ENST00000376020.9	NP_065768.2	Q9ULL8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHROOM4	ENST00000376020.9 link	c.436C>T	p.Arg146Trp	missense_variant	Exon 4 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.436C>T	p.Arg146Trp	missense_variant	Exon 4 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 3 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

109439

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00723

Gnomad SAS

AF:

0.00127

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0000572

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000680

AC:

124

AN:

182456

AF XY:

0.000746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00759

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000982

Gnomad OTH exome

AF:

0.000887

GnomAD4 exome

AF:

0.000188

AC:

206

AN:

1097314

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

AN XY:

362966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26380

American (AMR)

AF:

0.00

AC:

AN:

35185

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00424

AC:

128

AN:

30200

South Asian (SAS)

AF:

0.000426

AC:

AN:

54024

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00138

AC:

AN:

3622

European-Non Finnish (NFE)

AF:

0.0000439

AC:

AN:

841975

Other (OTH)

AF:

0.000261

AC:

AN:

46028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

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:

0.000301

AC:

AN:

109489

Hom.:

Cov.:

AF XY:

0.000346

AC XY:

AN XY:

31807

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

29985

American (AMR)

AF:

0.00

AC:

AN:

10326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00725

AC:

AN:

3448

South Asian (SAS)

AF:

0.00127

AC:

AN:

2356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5888

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000572

AC:

AN:

52486

Other (OTH)

AF:

0.00

AC:

AN:

1467

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000137

Hom.:

Bravo

AF:

0.000514

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked intellectual disability, Stocco dos Santos type

Uncertain:2

Nov 15, 2022

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SHROOM4-related disorder

Benign:1

Sep 24, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

May 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

T;T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.6

M;M;.

PhyloP100

2.9

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.29

MVP

0.76

MPC

0.47

ClinPred

0.076

GERP RS

6.1

Varity_R

0.65

gMVP

0.61

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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