19-11033308-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001387283.1(SMARCA4):c.3565C>T(p.Arg1189*) 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.01

Publications

10 publications found

Variant links:

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]

SMARCA4 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 6554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 26 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 26 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 26 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 26 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 26 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 27 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 26 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 26 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.3565C>T	p.Arg1189*	stop_gained	Exon 27 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.2977C>T	p.Arg993*	stop_gained	Exon 23 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.2209C>T	p.Arg737*	stop_gained	Exon 19 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.2290C>T	p.Arg764*	stop_gained	Exon 19 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.2050C>T	p.Arg684*	stop_gained	Exon 18 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.1918C>T	p.Arg640*	stop_gained	Exon 17 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.-180C>T		upstream_gene_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Pathogenic:3

Dec 06, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6554). 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). -

not provided

Pathogenic:1

Dec 19, 2018

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 20, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.92

PhyloP100

1.0

Vest4

0.98

GERP RS

4.7

PromoterAI

-0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over