rs139505007

Variant names:

• chr19-11058324-C-G
• rs139505007
• NM_001387283.1:c.4590C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11058324-C-G
• chr19-11058324-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001387283.1(SMARCA4):​c.4590C>G​(p.Tyr1530*) 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 (★). Synonymous variant affecting the same amino acid position (i.e. Y1530Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.54
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 19-11058324-C-G is Pathogenic according to our data. Variant chr19-11058324-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1741714.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4590C>G	p.Tyr1530*	stop_gained	Exon 32 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4494C>G	p.Tyr1498*	stop_gained	Exon 31 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4590C>G	p.Tyr1530*	stop_gained	Exon 32 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4494C>G	p.Tyr1498*	stop_gained	Exon 31 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4500C>G	p.Tyr1500*	stop_gained	Exon 31 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4404C>G	p.Tyr1468*	stop_gained	Exon 31 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4404C>G	p.Tyr1468*	stop_gained	Exon 30 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4404C>G	p.Tyr1468*	stop_gained	Exon 30 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4401C>G	p.Tyr1467*	stop_gained	Exon 31 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3915C>G	p.Tyr1305*	stop_gained	Exon 28 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3144C>G	p.Tyr1048*	stop_gained	Exon 24 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3126C>G	p.Tyr1042*	stop_gained	Exon 23 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2988C>G	p.Tyr996*	stop_gained	Exon 23 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2856C>G	p.Tyr952*	stop_gained	Exon 22 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.660C>G	p.Tyr220*	stop_gained	Exon 5 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 26, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y1530* pathogenic mutation (also known as c.4590C>G), located in coding exon 31 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 4590. This changes the amino acid from a tyrosine to a stop codon within coding exon 31. 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	0.57
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Benign	-0.0029
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.24	N
PhyloP100		-1.5
Vest4		0.97
GERP RS		-0.19
Mutation Taster		=6/194	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs139505007; hg19: chr19-11169000;