rs1344296942

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_001387283.1(SMARCA4):c.961G>A(p.Ala321Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000063 in 1,587,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A321P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 6.87

Publications

4 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4107586).

BP6

Variant 19-10987767-G-A is Benign according to our data. Variant chr19-10987767-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 470471.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.961G>A	p.Ala321Thr	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.961G>A	p.Ala321Thr	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.961G>A	p.Ala321Thr	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.961G>A	p.Ala321Thr	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.961G>A	p.Ala321Thr	missense_variant	Exon 6 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.961G>A	p.Ala321Thr	missense_variant	Exon 7 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.961G>A	p.Ala321Thr	missense_variant	Exon 6 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.961G>A	p.Ala321Thr	missense_variant	Exon 6 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.961G>A	p.Ala321Thr	missense_variant	Exon 7 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 3 of 32			ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150594

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:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000143

AC:

AN:

209320

AF XY:

0.00000866

show subpopulations

Gnomad AFR exome

AF:

0.0000861

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000626

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000557

AC:

AN:

1437248

Hom.:

Cov.:

AF XY:

0.00000560

AC XY:

AN XY:

713938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32884

American (AMR)

AF:

0.00

AC:

AN:

43044

Ashkenazi Jewish (ASJ)

AF:

0.0000390

AC:

AN:

25654

East Asian (EAS)

AF:

0.00

AC:

AN:

38758

South Asian (SAS)

AF:

0.0000474

AC:

AN:

84458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1097346

Other (OTH)

AF:

0.00

AC:

AN:

59324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

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:

0.0000133

AC:

AN:

150594

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40946

American (AMR)

AF:

0.00

AC:

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.000196

AC:

AN:

5098

South Asian (SAS)

AF:

0.00

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67528

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Jan 22, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 321 of the SMARCA4 protein (p.Ala321Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 470471). 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) has been performed at Invitae 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. -

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

- -

not specified

Benign:1

Dec 09, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jul 17, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

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

Eigen

Benign

0.12

Eigen_PC

Benign

0.047

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.41

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

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.8

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

PhyloP100

6.9

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.84

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

REVEL

Uncertain

0.39

Sift

Benign

0.18

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

Sift4G

Benign

0.54

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

Polyphen

0.98

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

Vest4

0.38

MutPred

0.28

Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);Gain of glycosylation at A321 (P = 5e-04);

MVP

0.70

MPC

0.42

ClinPred

0.77

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.12

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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