19-11034947-C-G

Variant names:

• chr19-11034947-C-G
• rs878854219
• NM_001387283.1:c.3985C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.3985C>G​(p.Arg1329Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3985C>G	p.Arg1329Gly	missense_variant	Exon 29 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3985C>G	p.Arg1329Gly	missense_variant	Exon 29 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3985C>G	p.Arg1329Gly	missense_variant	Exon 29 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3985C>G	p.Arg1329Gly	missense_variant	Exon 29 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3886C>G	p.Arg1296Gly	missense_variant	Exon 28 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3886C>G	p.Arg1296Gly	missense_variant	Exon 29 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3886C>G	p.Arg1296Gly	missense_variant	Exon 28 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3886C>G	p.Arg1296Gly	missense_variant	Exon 28 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3886C>G	p.Arg1296Gly	missense_variant	Exon 29 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3397C>G	p.Arg1133Gly	missense_variant	Exon 26 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2629C>G	p.Arg877Gly	missense_variant	Exon 22 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2611C>G	p.Arg871Gly	missense_variant	Exon 21 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2470C>G	p.Arg824Gly	missense_variant	Exon 21 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2338C>G	p.Arg780Gly	missense_variant	Exon 20 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.142C>G	p.Arg48Gly	missense_variant	Exon 3 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Jul 03, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces arginine with glycine at codon 1329 of the SMARCA4 protein (p.Arg1329Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.066	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.27	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.79	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.
Vest4		0.68
MutPred		0.31		Gain of loop (P = 0.0097);.;Gain of loop (P = 0.0097);.;.;.;.;.;.;.;Gain of loop (P = 0.0097);.;.;.;.;.;.;Gain of loop (P = 0.0097);.;.;.;.;
MVP		0.76
MPC		3.1
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.53
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs878854219; hg19: chr19-11145623;