19-10989339-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.1141C>T(p.Arg381Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,748 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R381R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.641

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 19-10989339-C-T is Pathogenic according to our data. Variant chr19-10989339-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 470230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1141C>T	p.Arg381Ter	stop_gained	7/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.1141C>T	p.Arg381Ter	stop_gained	7/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1141C>T	p.Arg381Ter	stop_gained	7/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.1141C>T	p.Arg381Ter	stop_gained	7/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2017	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SMARCA4 are known to be pathogenic. This particular variant has been reported in the literature in an individual affected with small cell carcinoma of the ovary (PMID: 24658002). This sequence change creates a premature translational stop signal at codon 381 (p.Arg381*) of the SMARCA4 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided	clinical testing	Cancer Genomics Laboratory, Texas Children's Hospital	Jun 01, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2023

The p.R381* pathogenic mutation (also known as c.1141C>T), located in coding exon 6 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 1141. This changes the amino acid from an arginine to a stop codon within coding exon 6. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in SMARCA4 are known to cause rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT); however, such associations with neurodevelopmental disorders 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). Based on the supporting evidence, this alteration is pathogenic for rhabdoid tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

SMARCA4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

The SMARCA4 c.1141C>T variant is predicted to result in premature protein termination (p.Arg381*). This variant was reported in an individual with small cell carcinoma of the ovary, hypercalcemic type (Witkowski et al. 2014. PubMed ID: 24658002). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Loss-of-function variants in SMARCA4 are expected to be pathogenic for rhabdoid tumor predisposition syndrome; however, the association of loss-of-function variants with Coffin-Siris syndrome is currently uncertain. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
Vest4		0.98
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs972341316; hg19: chr19-11100015; COSMIC: COSV60802547; COSMIC: COSV60802547;