19-11060110-G-T

Variant names:

• chr19-11060110-G-T
• rs372319442
• NM_001387283.1:c.4930G>T

Variant summary

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

The NM_003072.5(SMARCA4):​c.4834G>T​(p.Gly1612Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.81

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.4930G>T	p.Gly1644Cys	missense_variant	Exon 35 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4834G>T	p.Gly1612Cys	missense_variant	Exon 34 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4930G>T	p.Gly1644Cys	missense_variant	Exon 35 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4834G>T	p.Gly1612Cys	missense_variant	Exon 34 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4840G>T	p.Gly1614Cys	missense_variant	Exon 34 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4744G>T	p.Gly1582Cys	missense_variant	Exon 34 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4744G>T	p.Gly1582Cys	missense_variant	Exon 33 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4744G>T	p.Gly1582Cys	missense_variant	Exon 33 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4741G>T	p.Gly1581Cys	missense_variant	Exon 34 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4255G>T	p.Gly1419Cys	missense_variant	Exon 31 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3484G>T	p.Gly1162Cys	missense_variant	Exon 27 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3466G>T	p.Gly1156Cys	missense_variant	Exon 26 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3328G>T	p.Gly1110Cys	missense_variant	Exon 26 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3094G>T	p.Gly1032Cys	missense_variant	Exon 24 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.898G>T	p.Gly300Cys	missense_variant	Exon 7 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000440

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398690 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 689900

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: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 30, 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 1644 of the SMARCA4 protein (p.Gly1644Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 963845). 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

Jun 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1644C variant (also known as c.4930G>T), located in coding exon 34 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 4930. The glycine at codon 1644 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.077
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.92	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0080	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.38
MutPred		0.20		.;.;Loss of helix (P = 0.0104);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.0104);.;.;.;.;
MVP		0.96
MPC		2.2
ClinPred		0.92	D
GERP RS		0.41
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.47
gMVP		0.76

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: rs372319442; hg19: chr19-11170786;