rs1555754225

Positions:

• chr19-10986944-GCGTGCCCCC-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_003072.5(SMARCA4):​c.803_811delTGCCCCCCG​(p.Val268_Pro270del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000617 in 1,459,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.28

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 -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003072.5.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	5/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	5/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	5/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	5/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	5/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	6/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	5/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	5/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.803_811delTGCCCCCCG	p.Val268_Pro270del	disruptive_inframe_deletion	6/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.215_223delTGCCCCCCG	p.Val72_Pro74del	disruptive_inframe_deletion	2/32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459550 Hom.: 0 AF XY: 0.00000826 AC XY: 6 AN XY: 726220

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: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This variant, c.803_811del, results in the deletion of 3 amino acid(s) of the SMARCA4 protein (p.Val268_Pro270del), but otherwise preserves the integrity of the reading frame. 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: 480595). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2024

In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

The c.803_811delTGCCCCCCG variant (also known as p.V268_P270del) is located in coding exon 4 of the SMARCA4 gene. This variant results from an in-frame deletion of 9 nucleotides (TGCCCCCCG) at nucleotide positions 803 to 811. This results in the in-frame deletion of 3 amino acids (VPP) at codons 268 to 270. The deleted amino acid positions are well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

SMARCA4-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2024

The SMARCA4 c.803_811del9 variant is predicted to result in an in-frame deletion (p.Val268_Pro270del). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/480595/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555754225; hg19: chr19-11097620;