rs1555757536

Variant names:

• chr19-10991168-G-A
• rs1555757536
• NM_001387283.1:c.1264G>A

Variant summary

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

The NM_003072.5(SMARCA4):​c.1264G>A​(p.Val422Met) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.97

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.1264G>A	p.Val422Met	missense_variant	Exon 8 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1264G>A	p.Val422Met	missense_variant	Exon 8 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1264G>A	p.Val422Met	missense_variant	Exon 8 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1264G>A	p.Val422Met	missense_variant	Exon 8 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1264G>A	p.Val422Met	missense_variant	Exon 8 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1264G>A	p.Val422Met	missense_variant	Exon 9 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1264G>A	p.Val422Met	missense_variant	Exon 8 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1264G>A	p.Val422Met	missense_variant	Exon 8 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1264G>A	p.Val422Met	missense_variant	Exon 9 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.676G>A	p.Val226Met	missense_variant	Exon 5 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.-93G>A		upstream_gene_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.-9G>A		upstream_gene_variant				ENSP00000493615.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 Uncertain:1

Nov 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 422 of the SMARCA4 protein (p.Val422Met). This variant is not present in population databases (gnomAD no frequency). 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: 537793). 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. -

not provided Uncertain:1

Nov 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMARCA4 c.1264G>A (p.Val422Met) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V422M variant (also known as c.1264G>A), located in coding exon 7 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1264. The valine at codon 422 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.70	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.048	D;.;.;.;.;.;.;.;.;.;D;.;T;.;T;.;T;T
Sift4G	Benign	0.10	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.98	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.38
MutPred		0.42		Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);Gain of catalytic residue at V422 (P = 0.0057);
MVP		0.48
MPC		2.1
ClinPred		0.77	D
GERP RS		4.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.23
gMVP		0.94

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: rs1555757536; hg19: chr19-11101844;