19-11033308-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001387283.1(SMARCA4):c.3565C>T(p.Arg1189Ter) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.01

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11033308-C-T is Pathogenic according to our data. Variant chr19-11033308-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11033308-C-T is described in Lovd as [Likely_benign]. Variant chr19-11033308-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.3565C>T	p.Arg1189Ter	stop_gained	26/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.3565C>T	p.Arg1189Ter	stop_gained	26/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3565C>T	p.Arg1189Ter	stop_gained	26/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.3565C>T	p.Arg1189Ter	stop_gained	26/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 29, 2021	This premature translational stop signal has been observed in individual(s) with rhabdoid tumor predisposition syndrome (PMID: 20137775). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1189*) in the SMARCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6554). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 06, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2018

The R1189X variant in the SMARCA4 gene has been previously reported in two siblings with rhabdoid tumors (Schneppenheim 2010) as well as in a small cell carcinoma of the ovary, hypercalcemia type (Ramos 2014). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1189X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, the R1189X variant is considered a pathogenic variant, and its presence is consistent with a SMARCA4-related disorder. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2019

The p.R1189* pathogenic mutation (also known as c.3565C>T), located in coding exon 25 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 3565. This changes the amino acid from an arginine to a stop codon within coding exon 25. This mutation has been detected in two sisters with early-onset rhabdoid tumors and separately in a woman with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) (Schneppenheim R et al. Am. J. Hum. Genet., 2010 Feb;86:279-84; Ramos P et al. Nat. Genet., 2014 May;46:427-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
Vest4		0.98
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs267607070; hg19: chr19-11143984; COSMIC: COSV60811967; COSMIC: COSV60811967;