rs281875187

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003070.5(SMARCA2):c.3476G>A(p.Arg1159Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1159L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA2
NM_003070.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 10.0

Publications

11 publications found

Variant links:

Genes affected

SMARCA2 (HGNC:11098): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is highly similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, which contains a trinucleotide repeat (CAG) length polymorphism. [provided by RefSeq, Jan 2014]

SMARCA2 Gene-Disease associations (from GenCC):

intellectual disability-sparse hair-brachydactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

SMARCA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_003070.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-2115841-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30015.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 9-2115841-G-A is Pathogenic according to our data. Variant chr9-2115841-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMARCA2	NM_003070.5 link	c.3476G>A	p.Arg1159Gln	missense_variant	Exon 25 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2 link	c.3476G>A	p.Arg1159Gln	missense_variant	Exon 25 of 34		NP_001276325.1
SMARCA2	NM_139045.4 link	c.3476G>A	p.Arg1159Gln	missense_variant	Exon 25 of 33		NP_620614.2
SMARCA2	NM_001289397.2 link	c.3302G>A	p.Arg1101Gln	missense_variant	Exon 25 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8 link	c.3476G>A	p.Arg1159Gln	missense_variant	Exon 25 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 24, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate impaired differentiation of neural progenitor cells and inappropriate enhancer reorganization (PMID: 31375262); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24090879, 35811451, 22366787, 31375262) -

Nicolaides-Baraitser syndrome

Pathogenic:2

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

SMARCA2-related BAFopathy

Pathogenic:1

Jun 10, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

.;.;D;.;D

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

.;D;.;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

5.2

H;.;H;H;H

PhyloP100

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.7

D;.;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;.;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;.;D;D;D

Vest4

0.93

MutPred

0.90

Loss of MoRF binding (P = 0.0718);.;Loss of MoRF binding (P = 0.0718);Loss of MoRF binding (P = 0.0718);Loss of MoRF binding (P = 0.0718);

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

5.7

Varity_R

0.91

gMVP

1.0

Mutation Taster

=2/98

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over