19-11007899-TAGG-TAGGAGG

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_001387283.1(SMARCA4):c.2010_2012dupGGA(p.Glu671dup) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

SMARCA4
NM_001387283.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 6.76

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001387283.1. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.2010_2012dupGGA	p.Glu671dup	disruptive_inframe_insertion	Exon 14 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.2010_2012dupGGA	p.Glu671dup	disruptive_inframe_insertion	Exon 14 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.2002-3_2002-2insAGG	splice_acceptor_variant, intron_variant	Intron 13 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.2002-3_2002-2insAGG	splice_acceptor_variant, intron_variant	Intron 13 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.2002-3_2002-2insAGG	splice_acceptor_variant, intron_variant	Intron 13 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.2002-3_2002-2insAGG	splice_acceptor_variant, intron_variant	Intron 14 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.2002-3_2002-2insAGG	splice_acceptor_variant, intron_variant	Intron 13 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.2002-3_2002-2insAGG	splice_acceptor_variant, intron_variant	Intron 13 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.2002-3_2002-2insAGG	splice_acceptor_variant, intron_variant	Intron 14 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.1414-3_1414-2insAGG	splice_acceptor_variant, intron_variant	Intron 10 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.646-3_646-2insAGG	splice_acceptor_variant, intron_variant	Intron 6 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.727-3_727-2insAGG	splice_acceptor_variant, intron_variant	Intron 6 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.487-3_487-2insAGG	splice_acceptor_variant, intron_variant	Intron 5 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.355-3_355-2insAGG	splice_acceptor_variant, intron_variant	Intron 4 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 24, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this 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: 27535533) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jun 27, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2010_2012dupGGA variant (also known as p.E672dup), located in coding exon 13 of the SMARCA4 gene, results from an in-frame duplication of GGA at nucleotide positions 2010 to 2012. This results in the duplication of an extra glutamic acid residue between codons 672 and 673. The duplicated amino acid position is well conserved in available vertebrate species. 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

PhyloP100

6.8

Splicing

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