chr19-10989339-C-G

Position:

• chr19-10989339-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The ENST00000344626.10(SMARCA4):​c.1141C>G​(p.Arg381Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R381Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 ENST00000344626.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.641

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1141C>G	p.Arg381Gly	missense_variant	7/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1141C>G	p.Arg381Gly	missense_variant	7/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1141C>G	p.Arg381Gly	missense_variant	7/36		NM_001387283.1	ENSP00000495368
SMARCA4	ENST00000344626.10	c.1141C>G	p.Arg381Gly	missense_variant	7/35	1	NM_003072.5	ENSP00000343896	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2024

The p.R381G variant (also known as c.1141C>G), located in coding exon 6 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 1141. The arginine at codon 381 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	2.0	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.88
MutPred		0.75		Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);Loss of MoRF binding (P = 0.0368);
MVP		0.95
MPC		2.8
ClinPred		0.96	D
GERP RS		1.9
Varity_R		0.96
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11100015;