rs875989800

Positions:

• chr22-23833669-GAGA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_003073.5(SMARCB1):​c.1091_1093del​(p.Lys364del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.03

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003073.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 22-23833669-GAGA-G is Pathogenic according to our data. Variant chr22-23833669-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 30201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23833669-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.1091_1093del	p.Lys364del	inframe_deletion	8/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001007468.3	c.1064_1066del	p.Lys355del	inframe_deletion	8/9		NP_001007469.1
SMARCB1	NM_001317946.2	c.1118_1120del	p.Lys373del	inframe_deletion	8/9		NP_001304875.1
SMARCB1	NM_001362877.2	c.1145_1147del	p.Lys382del	inframe_deletion	8/9		NP_001349806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1091_1093del	p.Lys364del	inframe_deletion	8/9		NM_003073.5	ENSP00000494049	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727222

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Recurrent de novo pathogenic variant; affected persons had strikingly similar clinical manifestations. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are all known mechanisms of disease in this gene. Loss of function variants are associated with cancer susceptibility (rhabdoid tumor predisposition syndrome 1 (MIM#609322), schwannomatosis-1 (MIM#162091), rhabdoid tumors somatic (MIM#609322)). An inframe deletion variant, missense variants and truncating variants escaping nonsense-mediated decay have been reported to have either a gain of function or dominant negative mechanism, and are all associated with Coffin-Siris syndrome 3 (MIM#614608) (OMIM, PMID: 31759698). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER, PMID: 31759698). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and de novo in individuals with Coffin-Siris syndrome (PMID: 31759698, ClinVar, DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 18, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2022	This variant has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 22426308, 23815551, 23929686, 25533962). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 30201). This variant is not present in population databases (gnomAD no frequency). This variant, c.1091_1093del, results in the deletion of 1 amino acid(s) of the SMARCB1 protein (p.Lys364del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2016	The c.1091_1093delAGA variant in the SMARCB1 gene is a recurrent pathogenic variant seen in individuals with Coffin-Siris syndrome (Tsurusaki et al., 2012; Santen et al., 2013; Kosho et al., 2014; Tsurusaki et al., 2014). The c.1091_1093delAGA variant causes an in-frame deletion of codon Lysine 364, denoted p.Lys364del. The c.1091_1093delAGA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1091_1093delAGA as a pathogenic variant. -

Rhabdoid tumor predisposition syndrome 1;C3553248:Intellectual disability, autosomal dominant 15;C4048809:Schwannomatosis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2023

The c.1091_1093delAGA (p.K364del) alteration, located in coding exon 8 of the SMARCB1 gene, results from an in-frame deletion of 3 nucleotides at positions c.1091 toc.1093. This results in the deletion of 1 amino acid at codon 364. _x000D_ _x000D_ Based on the available evidence, the SMARCB1 c.1091_1093delAGA (p.K364del) alteration is classified as pathogenic for SMARCB1-related Coffin-Siris syndrome; however, its clinical significance for SMARCB1-related tumor predisposition syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with a clinical diagnosis of Coffin-Siris syndrome, including several with confirmed de novo origin (Tsurusaki, 2012; Santen, 2013; Kosho, 2013; Kosho, 2014; Miyake, 2014; Sekiguchi, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro and cell-based functional studies demonstrated this alteration results in reduced mSWI/SNF functional activity and is defective in generating DNA accessibility and in activating critical target genes (Valencia, 2019). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs875989800; hg19: chr22-24175856;