NM_001387283.1:c.2860-1G>A

Variant names:

• chr19-11023517-G-A
• rs1060502102
• NM_001387283.1:c.2860-1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001387283.1(SMARCA4):​c.2860-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.76
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022619048 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11023517-G-A is Pathogenic according to our data. Variant chr19-11023517-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 408702.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.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 20 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2860-1G>A		splice_acceptor_variant, intron_variant	Intron 20 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2272-1G>A		splice_acceptor_variant, intron_variant	Intron 16 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1504-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1585-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1345-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1213-1G>A		splice_acceptor_variant, intron_variant	Intron 10 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:1

Jun 21, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMARCA4-related disease. This sequence change affects an acceptor splice site in intron 19 of the SMARCA4 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		9.8
GERP RS		4.9
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: 2
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060502102; hg19: chr19-11134193;