rs1060502076

Variant names:

• chr19-11033753-CTATT-C
• rs1060502076
• NM_001387283.1:c.3775-10_3775-7delTTAT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003072.5(SMARCA4):​c.3775-10_3775-7delTTAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 627,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

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]

ENSG00000278643 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3775-10_3775-7delTTAT		splice_region_variant, intron_variant	Intron 26 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3775-10_3775-7delTTAT		splice_region_variant, intron_variant	Intron 26 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3775-10_3775-7delTTAT		splice_region_variant, intron_variant	Intron 26 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3775-10_3775-7delTTAT		splice_region_variant, intron_variant	Intron 26 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3774+240_3774+243delTTAT		intron_variant	Intron 26 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3774+240_3774+243delTTAT		intron_variant	Intron 27 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3774+240_3774+243delTTAT		intron_variant	Intron 26 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3774+240_3774+243delTTAT		intron_variant	Intron 26 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3774+240_3774+243delTTAT		intron_variant	Intron 27 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3187-10_3187-7delTTAT		splice_region_variant, intron_variant	Intron 23 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2419-10_2419-7delTTAT		splice_region_variant, intron_variant	Intron 19 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2499+240_2499+243delTTAT		intron_variant	Intron 19 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2260-10_2260-7delTTAT		splice_region_variant, intron_variant	Intron 18 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2128-10_2128-7delTTAT		splice_region_variant, intron_variant	Intron 17 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.30+240_30+243delTTAT		intron_variant	Intron 1 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000159 AC: 1 AN: 627826 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 342054

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: 0.0000193

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 26 of the SMARCA4 gene. It does not directly change the encoded amino acid sequence of the SMARCA4 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 408636). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: -34

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502076; hg19: chr19-11144429;