rs372601826

chr19-10986523-CGGCCCTGGCCCT-Cchr19-10986523-CGGCCCTGGCCCT-CGGCCCTchr19-10986523-CGGCCCTGGCCCT-CGGCCCTGGCCCTGGCCCTchr19-10986523-CGGCCCTGGCCCT-CGGCCCTGGCCCTGGCCCTGGCCCT

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_001387283.1(SMARCA4):c.702_713del(p.Gly241_Pro244del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000415 in 1,543,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G231G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.83

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 Benign. Variant got -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001387283.1
• BP6: Variant 19-10986523-CGGCCCTGGCCCT-C is Benign according to our data. Variant chr19-10986523-CGGCCCTGGCCCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 408652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.702_713del	p.Gly241_Pro244del	inframe_deletion	4/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.702_713del	p.Gly241_Pro244del	inframe_deletion	4/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000344626.10	c.702_713del	p.Gly241_Pro244del	inframe_deletion	4/35	1	NM_003072.5	P4
SMARCA4	ENST00000646693.2	c.702_713del	p.Gly241_Pro244del	inframe_deletion	4/36		NM_001387283.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000933 AC: 13 AN: 139340 Hom.: 0 AF XY: 0.0000661 AC XY: 5 AN XY: 75650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000286

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.0000924

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000338 AC: 47 AN: 1391208 Hom.: 0 AF XY: 0.0000364 AC XY: 25 AN XY: 686496

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000742

Gnomad4 OTH exome AF: 0.0000863

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74346

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2021

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs372601826; hg19: chr19-11097199;