rs568390760

Positions:

• chr19-10986544-CCCCGGCCCGGGT-C
• chr19-10986544-CCCCGGCCCGGGT-CCCCGGCCCGGGTCCCGGCCCGGGT

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001387283.1(SMARCA4):​c.722_733del​(p.Gly241_Pro244del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000129 in 1,540,212 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P238P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (1 hom.)
• Consequence: SMARCA4 NM_001387283.1 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6 O:1
• Conservation: PhyloP100: 6.17

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001387283.1
• BP6: Variant 19-10986544-CCCCGGCCCGGGT-C is Benign according to our data. Variant chr19-10986544-CCCCGGCCCGGGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 238517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10986544-CCCCGGCCCGGGT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000565 (86/152222) while in subpopulation AFR AF= 0.00195 (81/41552). AF 95% confidence interval is 0.00161. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.722_733del	p.Gly241_Pro244del	inframe_deletion	4/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.722_733del	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.722_733del	p.Gly241_Pro244del	inframe_deletion	4/35	1	NM_003072.5	P4
SMARCA4	ENST00000646693.2	c.722_733del	p.Gly241_Pro244del	inframe_deletion	4/36		NM_001387283.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 14 AN: 134992 Hom.: 0 AF XY: 0.0000542 AC XY: 4 AN XY: 73738

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000488

GnomAD4 exome AF: 0.0000814 AC: 113 AN: 1387990 Hom.: 1 AF XY: 0.0000657 AC XY: 45 AN XY: 684998

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.000242

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74412

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000650

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2022	See Variant Classification Assertion Criteria. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SMARCA4 p.Gly241_Pro244del variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs568390760) and in ClinVar (classified as likely benign by Genetic Services Laboratory University of Chicago and Ambry Genetics and as VUS by Invitae). The variant was identified in control databases in 27 of 166304 chromosomes at a frequency of 0.000162 (Genome Aggregation Database Feb 27, 2017). The variant was found in the following populations: African in 22 of 15130 chromosomes (freq: 0.001454), Other in 2 of 5186 chromosomes (freq: 0.000386) and Latino in 3 of 25264 chromosomes (freq: 0.000119), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant is an in-frame deletion resulting in the removal of codons 241 to 244 in a proline-glycine repeat region, however the impact of this alteration on the SMARCA4 protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 29, 2022	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2018	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. -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 14, 2016	- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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: rs568390760; hg19: chr19-11097220;