chr22-23791865-ATGGTAAAAAAACA-TACC

Position:

• chr22-23791865-ATGGTAAAAAAACA-TACC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP2 PP5

The NM_001317946.2(SMARCB1):​c.203_205+11delATGGTAAAAAAACAinsTACC​(p.Asp69del) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_001317946.2 splice_donor, missense, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.70

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.2, offset of 17, new splice context is: aggGTgcgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCB1. . Gene score misZ 3.6016 (greater than the threshold 3.09). Trascript score misZ 4.8413 (greater than threshold 3.09). GenCC has associacion of gene with schwannomatosis 1, familial multiple meningioma, rhabdoid tumor predisposition syndrome 1, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 15, familial rhabdoid tumor, schwannomatosis, Coffin-Siris syndrome.
• PP5: Variant 22-23791865-ATGGTAAAAAAACA-TACC is Pathogenic according to our data. Variant chr22-23791865-ATGGTAAAAAAACA-TACC is described in ClinVar as [Pathogenic]. Clinvar id is 8028.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.203_216delATGGTAAAAAAACAinsTACC	p.His68fs	frameshift_variant, missense_variant	2/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.203_216delATGGTAAAAAAACAinsTACC	p.His68fs	frameshift_variant, missense_variant	2/9		NP_001349806.1
SMARCB1	NM_001317946.2	c.203_205+11delATGGTAAAAAAACAinsTACC	p.Asp69del	splice_donor_variant, missense_variant, splice_region_variant, intron_variant			NP_001304875.1
SMARCB1	NM_001007468.3	c.203_205+11delATGGTAAAAAAACAinsTACC	p.Asp69del	splice_donor_variant, missense_variant, splice_region_variant, intron_variant			NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.203_216delATGGTAAAAAAACAinsTACC	p.His68fs	frameshift_variant, missense_variant	2/9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

SMARCB1-related schwannomatosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

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: rs587776679; hg19: chr22-24134052;