chr19-11008010-C-T

Variant names:

• chr19-11008010-C-T
• rs781539973
• NM_001387283.1:c.2110C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_003072.5(SMARCA4):​c.2110C>T​(p.Arg704Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.931

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 Likely_benign. Variant got -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2110C>T	p.Arg704Trp	missense_variant	Exon 14 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2110C>T	p.Arg704Trp	missense_variant	Exon 14 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2110C>T	p.Arg704Trp	missense_variant	Exon 14 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2110C>T	p.Arg704Trp	missense_variant	Exon 14 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2110C>T	p.Arg704Trp	missense_variant	Exon 14 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2110C>T	p.Arg704Trp	missense_variant	Exon 15 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2110C>T	p.Arg704Trp	missense_variant	Exon 14 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2110C>T	p.Arg704Trp	missense_variant	Exon 14 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2110C>T	p.Arg704Trp	missense_variant	Exon 15 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1522C>T	p.Arg508Trp	missense_variant	Exon 11 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.754C>T	p.Arg252Trp	missense_variant	Exon 7 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.835C>T	p.Arg279Trp	missense_variant	Exon 7 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.595C>T	p.Arg199Trp	missense_variant	Exon 6 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.463C>T	p.Arg155Trp	missense_variant	Exon 5 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250456 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135376

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460950 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74296

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Dec 14, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 704 of the SMARCA4 protein (p.Arg704Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 408645). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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. -

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

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2110C>T (p.R704W) alteration is located in exon 14 (coding exon 13) of the SMARCA4 gene. This alteration results from a C to T substitution at nucleotide position 2110, causing the arginine (R) at amino acid position 704 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.
Polyphen		0.99	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.
Vest4		0.58
MutPred		0.39		Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);.;Loss of disorder (P = 0.005);.;.;.;
MVP		0.86
MPC		2.0
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.28
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs781539973; hg19: chr19-11118686; COSMIC: COSV100759198; COSMIC: COSV100759198;