rs1555877276

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003073.5(SMARCB1):​c.501-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 34)

Consequence

SMARCB1
NM_003073.5 splice_acceptor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.99
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]

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ACMG classification

Classification made for transcript

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 5.4, offset of -44, new splice context is: ctgaaaatttgcatacctAGggc. 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;
PP5
Variant 22-23803294-G-C is Pathogenic according to our data. Variant chr22-23803294-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 464328.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCB1NM_003073.5 linkuse as main transcriptc.501-1G>C splice_acceptor_variant, intron_variant ENST00000644036.2 NP_003064.2 Q12824-1
SMARCB1NM_001362877.2 linkuse as main transcriptc.555-1G>C splice_acceptor_variant, intron_variant NP_001349806.1
SMARCB1NM_001317946.2 linkuse as main transcriptc.528-1G>C splice_acceptor_variant, intron_variant NP_001304875.1 G5E975Q9H836
SMARCB1NM_001007468.3 linkuse as main transcriptc.474-1G>C splice_acceptor_variant, intron_variant NP_001007469.1 Q12824-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCB1ENST00000644036.2 linkuse as main transcriptc.501-1G>C splice_acceptor_variant, intron_variant NM_003073.5 ENSP00000494049.2 Q12824-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 01, 2017For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMARCB1 are known to be pathogenic (PMID: 10521299, 21208904). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Family studies have indicated that this variant was not present in the parents of an affected individual, which suggests that it was de novo in that affected individual (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the SMARCB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Uncertain
0.93
D
GERP RS
4.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.87
Position offset: 21
DS_AL_spliceai
1.0
Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555877276; hg19: chr22-24145481; COSMIC: COSV54098194; COSMIC: COSV54098194; API