19-10986524-G-T

Variant names:

• chr19-10986524-G-T
• rs555467836
• NM_001387283.1:c.691G>T

Variant summary

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

The NM_003072.5(SMARCA4):​c.691G>T​(p.Gly231Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G231S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.83

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.691G>T	p.Gly231Cys	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.691G>T	p.Gly231Cys	missense_variant	Exon 4 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.691G>T	p.Gly231Cys	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.691G>T	p.Gly231Cys	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.691G>T	p.Gly231Cys	missense_variant	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.691G>T	p.Gly231Cys	missense_variant	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.691G>T	p.Gly231Cys	missense_variant	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.691G>T	p.Gly231Cys	missense_variant	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.691G>T	p.Gly231Cys	missense_variant	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.103G>T	p.Gly35Cys	missense_variant	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1388800 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 685440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Apr 08, 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 cysteine, which is neutral and slightly polar, at codon 231 of the SMARCA4 protein (p.Gly231Cys). 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: 855570). 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

May 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G231C variant (also known as c.691G>T), located in coding exon 3 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 691. The glycine at codon 231 is replaced by cysteine, an amino acid with highly dissimilar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.012	D;.;.;.;.;.;.;.;.;.;D;.;T;.;T;.;T;T
Sift4G	Uncertain	0.031	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen		0.84	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P
Vest4		0.69
MutPred		0.30		Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);Gain of catalytic residue at P230 (P = 0.0104);
MVP		0.71
MPC		0.93
ClinPred		0.83	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.15
gMVP		0.23

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: rs555467836; hg19: chr19-11097200;