rs757412819

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001387283.1(SMARCA4):c.4972G>A(p.Val1658Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000193 in 1,551,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1658L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 6.83

Publications

1 publications found

Variant links:

COSMIC-nc: COSV100758183

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is 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. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4972G>A	p.Val1658Met	missense_variant	Exon 35 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4876G>A	p.Val1626Met	missense_variant	Exon 34 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.4972G>A	p.Val1658Met	missense_variant	Exon 35 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.4876G>A	p.Val1626Met	missense_variant	Exon 34 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.4882G>A	p.Val1628Met	missense_variant	Exon 34 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.4786G>A	p.Val1596Met	missense_variant	Exon 34 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.4786G>A	p.Val1596Met	missense_variant	Exon 33 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.4786G>A	p.Val1596Met	missense_variant	Exon 33 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.4783G>A	p.Val1595Met	missense_variant	Exon 34 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.4297G>A	p.Val1433Met	missense_variant	Exon 31 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.3526G>A	p.Val1176Met	missense_variant	Exon 27 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.3508G>A	p.Val1170Met	missense_variant	Exon 26 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.3370G>A	p.Val1124Met	missense_variant	Exon 26 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.3136G>A	p.Val1046Met	missense_variant	Exon 24 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.940G>A	p.Val314Met	missense_variant	Exon 7 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000129

AC:

AN:

155448

AF XY:

0.0000122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000207

AC:

AN:

1398848

Hom.:

Cov.:

AF XY:

0.0000203

AC XY:

AN XY:

689970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31584

American (AMR)

AF:

0.00

AC:

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.0000260

AC:

AN:

1078678

Other (OTH)

AF:

0.00

AC:

AN:

57968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000143

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 16

Uncertain:2

Apr 16, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1658 of the SMARCA4 protein (p.Val1658Met). This variant is present in population databases (rs757412819, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 408703). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 11, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

Dec 29, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SMARCA4 c.4972G>A (p.Val1658Met) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. The frequency of this variant in the general population, 0.000013 (2/155448 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Aug 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Dec 19, 2022

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. -

Dec 17, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SMARCA4-related disorder

Uncertain:1

Jun 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SMARCA4 c.4972G>A variant is predicted to result in the amino acid substitution p.Val1658Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/408703/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

6.8

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.4

N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.

Sift4G

Benign

0.080

T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.

Polyphen

0.90

P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.

Vest4

0.42

MVP

0.80

MPC

1.5

ClinPred

0.84

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.51

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over