rs1333494917

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7

The NM_001387283.1(SMARCA4):c.3792G>A(p.Thr1264Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000478 in 627,700 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).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.85

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:

ENSG00000278643 (HGNC:):

ENSG00000278643 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 19-11033784-G-A is Benign according to our data. Variant chr19-11033784-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 537890.

BP7

Synonymous conserved (PhyloP=1.85 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.3792G>A	p.Thr1264Thr	synonymous_variant	Exon 27 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3792G>A	p.Thr1264Thr	synonymous_variant	Exon 27 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.3792G>A	p.Thr1264Thr	synonymous_variant	Exon 27 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.3792G>A	p.Thr1264Thr	synonymous_variant	Exon 27 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643995.1 link	c.3204G>A	p.Thr1068Thr	synonymous_variant	Exon 24 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.2436G>A	p.Thr812Thr	synonymous_variant	Exon 20 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000642350.1 link	c.2277G>A	p.Thr759Thr	synonymous_variant	Exon 19 of 27			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.2145G>A	p.Thr715Thr	synonymous_variant	Exon 18 of 25			ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000643549.1 link	c.3774+267G>A		intron_variant	Intron 26 of 34			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.3774+267G>A		intron_variant	Intron 27 of 34	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.3774+267G>A		intron_variant	Intron 26 of 33			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.3774+267G>A		intron_variant	Intron 26 of 33			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.3774+267G>A		intron_variant	Intron 27 of 34	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000644065.1 link	c.2499+267G>A		intron_variant	Intron 19 of 26			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000538456.4 link	c.30+267G>A		intron_variant	Intron 1 of 7	3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246006

AF XY:

0.00000745

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:

0.00000915

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000478

AC:

AN:

627700

Hom.:

Cov.:

AF XY:

0.00000585

AC XY:

AN XY:

341988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17700

American (AMR)

AF:

0.00

AC:

AN:

43734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20988

East Asian (EAS)

AF:

0.00

AC:

AN:

36070

South Asian (SAS)

AF:

0.0000143

AC:

AN:

69804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

0.00000571

AC:

AN:

350268

Other (OTH)

AF:

0.00

AC:

AN:

33082

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 08, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jan 19, 2018

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

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

1.8

PromoterAI

0.069

Neutral

(source)

Mutation Taster

=100/0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over