rs1064795842

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001387283.1(SMARCA4):c.778A>C(p.Met260Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,268 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M260V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 8.38

Publications

1 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: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000395 (6/152016) while in subpopulation NFE AF = 0.0000883 (6/67974). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.778A>C	p.Met260Leu	missense_variant	Exon 5 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.778A>C	p.Met260Leu	missense_variant	Exon 5 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.778A>C	p.Met260Leu	missense_variant	Exon 5 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.778A>C	p.Met260Leu	missense_variant	Exon 5 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.778A>C	p.Met260Leu	missense_variant	Exon 5 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.778A>C	p.Met260Leu	missense_variant	Exon 6 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.778A>C	p.Met260Leu	missense_variant	Exon 5 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.778A>C	p.Met260Leu	missense_variant	Exon 5 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.778A>C	p.Met260Leu	missense_variant	Exon 6 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.190A>C	p.Met64Leu	missense_variant	Exon 2 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152016

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250088

AF XY:

0.00000739

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1460252

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000414

AC:

AN:

1111454

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000395

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 04, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SMARCA4 c.778A>C (p.Met260Leu) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. The frequency of this variant in the general population, 0.00004 (2/50380 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. -

Dec 30, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27930734) -

Mar 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Jan 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 260 of the SMARCA4 protein (p.Met260Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 422533). 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 with a negative predictive value of 95%. 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. -

Sep 19, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Mar 04, 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. -

Nov 16, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Intellectual disability, autosomal dominant 16

Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.28

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

Eigen

Benign

-0.12

Eigen_PC

Benign

0.049

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.44

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

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.

PhyloP100

8.4

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.78

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

REVEL

Uncertain

0.37

Sift

Benign

0.62

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

Sift4G

Benign

0.93

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

Polyphen

0.0020

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

Vest4

0.47

MutPred

0.27

Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);

MVP

0.90

MPC

0.24

ClinPred

0.79

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.29

gMVP

0.033

Mutation Taster

=73/27

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