chr13-48379592-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000321.3(RB1):​c.1333-2A>G 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: 30)

Consequence

RB1
NM_000321.3 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.47
Variant links:
Genes affected
RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

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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, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02009329 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of -33, new splice context is: attgtgattttctaaaatAGcag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-48379592-A-G is Pathogenic according to our data. Variant chr13-48379592-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 458120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RB1NM_000321.3 linkuse as main transcriptc.1333-2A>G splice_acceptor_variant, intron_variant ENST00000267163.6 NP_000312.2 P06400A0A024RDV3
RB1NM_001407165.1 linkuse as main transcriptc.1333-2A>G splice_acceptor_variant, intron_variant NP_001394094.1
RB1NM_001407166.1 linkuse as main transcriptc.1333-2A>G splice_acceptor_variant, intron_variant NP_001394095.1
LOC112268118XR_002957522.2 linkuse as main transcriptn.40+243T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.1333-2A>G splice_acceptor_variant, intron_variant 1 NM_000321.3 ENSP00000267163.4 P06400
RB1ENST00000650461.1 linkuse as main transcriptc.1333-2A>G splice_acceptor_variant, intron_variant ENSP00000497193.1 A0A3B3IS71

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinoblastoma Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 05, 2017Loss-of-function variants in RB1 are known to be pathogenic. This particular variant has been reported in several individuals affected with retinoblastoma in the literature (PMID: 12541220) and in the Leiden Open-source Variation Database (PMID: 21520333). This variant is also known as 1471-2A>G in the literature. This sequence change affects an acceptor splice site in intron 13 of the RB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterresearchDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDec 15, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
32
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.96
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.96
Position offset: 2

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: rs1555286503; hg19: chr13-48953728; COSMIC: COSV57301529; COSMIC: COSV57301529; API