rs140192268

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.1114T>A(p.Tyr372Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,294 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. Y372H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.14

Publications

0 publications found

Variant links:

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.1114T>A	p.Tyr372Asn	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 6 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 6 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 7 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 6 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 6 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.1114T>A	p.Tyr372Asn	missense_variant	Exon 7 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.526T>A	p.Tyr176Asn	missense_variant	Exon 3 of 32			ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460294

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5126

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Sep 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 372 of the SMARCA4 protein (p.Tyr372Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y372N variant (also known as c.1114T>A), located in coding exon 5 of the SMARCA4 gene, results from a T to A substitution at nucleotide position 1114. The tyrosine at codon 372 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.17

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.085

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.094

MetaRNN

Uncertain

0.45

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.1

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

PhyloP100

6.1

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.010

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

REVEL

Uncertain

0.50

Sift

Benign

0.37

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

Sift4G

Benign

0.35

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

Polyphen

0.0020

B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B

Vest4

0.80

MutPred

0.41

Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);

MVP

0.98

MPC

2.8

ClinPred

0.81

GERP RS

4.5

Varity_R

0.21

gMVP

0.91

Mutation Taster

=11/89

disease causing

(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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rs140192268

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