19-10986455-C-T

Variant names:

• chr19-10986455-C-T
• rs748298484
• NM_001387283.1:c.622C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_003072.5(SMARCA4):​c.622C>T​(p.Arg208Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000641 in 1,560,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.38

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 -2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• 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.622C>T	p.Arg208Trp	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.622C>T	p.Arg208Trp	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.622C>T	p.Arg208Trp	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.622C>T	p.Arg208Trp	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.622C>T	p.Arg208Trp	missense_variant	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.622C>T	p.Arg208Trp	missense_variant	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.622C>T	p.Arg208Trp	missense_variant	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.622C>T	p.Arg208Trp	missense_variant	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.622C>T	p.Arg208Trp	missense_variant	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.34C>T	p.Arg12Trp	missense_variant	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 9 AN: 1408004 Hom.: 0 Cov.: 34 AF XY: 0.00000862 AC XY: 6 AN XY: 695654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000548

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: 0.00000645

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000173 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Oct 09, 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 208 of the SMARCA4 protein (p.Arg208Trp). 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: 484934). 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. -

Dec 19, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Uncertain:1

Jan 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000066 (1/152208 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R208W variant (also known as c.622C>T), located in coding exon 3 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 622. The arginine at codon 208 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in multiple individuals with no reported features of SMARCA4-associated Coffin-Siris syndrome (Ambry internal data). 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 rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.83
MutPred		0.40		Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);Gain of catalytic residue at P211 (P = 0.0333);
MVP		0.80
MPC		0.91
ClinPred		0.99	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.43

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: rs748298484; hg19: chr19-11097131; COSMIC: COSV104654038; COSMIC: COSV104654038;