rs960893176

Variant names:

• chr19-10996496-G-A
• rs960893176
• NM_001387283.1:c.1764G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10996496-G-A
• chr19-10996496-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Moderate PM2 BP6_Very_Strong

The ENST00000644065.1(SMARCA4):​c.490-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 ENST00000644065.1 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.43

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 Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013415316 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of -3, new splice context is: gtgtctctctctatttccAGaaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-10996496-G-A is Benign according to our data. Variant chr19-10996496-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 415127.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	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 11 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 11 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 11 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 11 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 11 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 12 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 11 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 11 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1764G>A	p.Lys588Lys	splice_region_variant, synonymous_variant	Exon 12 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1176G>A	p.Lys392Lys	splice_region_variant, synonymous_variant	Exon 8 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.408G>A	p.Lys136Lys	splice_region_variant, synonymous_variant	Exon 4 of 28			ENSP00000495599.1
SMARCA4	ENST00000643857.1	c.117G>A	p.Lys39Lys	splice_region_variant, synonymous_variant	Exon 2 of 25			ENSP00000494159.1
SMARCA4	ENST00000644065.1	c.490-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.250-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 26			ENSP00000495355.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 04, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.94
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs960893176; hg19: chr19-11107172;