rs875989800

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_003073.5(SMARCB1):c.1091_1093delAGA(p.Lys364del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.03

Publications

24 publications found

Variant links:

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]

SMARCB1 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
intellectual disability, autosomal dominant 15
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
rhabdoid tumor predisposition syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
SMARCB1-related schwannomatosis
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
familial multiple meningioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
schwannomatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SMARCB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003073.5

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 VariationId is 30201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMARCB1	NM_003073.5 link	c.1091_1093delAGA	p.Lys364del	disruptive_inframe_deletion	Exon 8 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2 link	c.1145_1147delAGA	p.Lys382del	disruptive_inframe_deletion	Exon 8 of 9		NP_001349806.1
SMARCB1	NM_001317946.2 link	c.1118_1120delAGA	p.Lys373del	disruptive_inframe_deletion	Exon 8 of 9		NP_001304875.1
SMARCB1	NM_001007468.3 link	c.1064_1066delAGA	p.Lys355del	disruptive_inframe_deletion	Exon 8 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2 link	c.1091_1093delAGA	p.Lys364del	disruptive_inframe_deletion	Exon 8 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461840

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 15

Pathogenic:5Other:1

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Sep 08, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Recurrent de novo pathogenic variant; affected persons had strikingly similar clinical manifestations. -

Mar 18, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 11, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

May 02, 2016

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 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. 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. -

Rhabdoid tumor predisposition syndrome 1;C3553248:Intellectual disability, autosomal dominant 15;C4048809:SMARCB1-related schwannomatosis

Pathogenic:1

Apr 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 06, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.0

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over