NM_001387283.1:c.1982G>T

Variant names:

• chr19-11003378-G-T
• rs367689657
• NM_001387283.1:c.1982G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001387283.1(SMARCA4):​c.1982G>T​(p.Gly661Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G661D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.93
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21091667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1982G>T	p.Gly661Val	missense_variant	Exon 13 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1982G>T	p.Gly661Val	missense_variant	Exon 13 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1982G>T	p.Gly661Val	missense_variant	Exon 13 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1982G>T	p.Gly661Val	missense_variant	Exon 13 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1982G>T	p.Gly661Val	missense_variant	Exon 13 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1982G>T	p.Gly661Val	missense_variant	Exon 14 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1982G>T	p.Gly661Val	missense_variant	Exon 13 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1982G>T	p.Gly661Val	missense_variant	Exon 13 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1982G>T	p.Gly661Val	missense_variant	Exon 14 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1394G>T	p.Gly465Val	missense_variant	Exon 10 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.626G>T	p.Gly209Val	missense_variant	Exon 6 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.707G>T	p.Gly236Val	missense_variant	Exon 6 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.467G>T	p.Gly156Val	missense_variant	Exon 5 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.335G>T	p.Gly112Val	missense_variant	Exon 4 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 661 of the SMARCA4 protein (p.Gly661Val). 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: 571010). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G661V variant (also known as c.1982G>T), located in coding exon 12 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 1982. The glycine at codon 661 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.046
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PhyloP100		2.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.29	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.;.
Sift4G	Benign	0.063	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;D;T;.;.;.;.
Polyphen		0.47	P;.;B;.;.;.;.;.;.;.;P;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.49
MutPred		0.22		Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);.;Loss of relative solvent accessibility (P = 0.008);.;.;.;.;
MVP		0.61
MPC		2.1
ClinPred		0.92	D
GERP RS		3.2
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.13
gMVP		0.74
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs367689657; hg19: chr19-11114054;