rs1131690892
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_000321.3(RB1):c.1128-2A>G variant causes a splice acceptor change. 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: 32)
Consequence
RB1
NM_000321.3 splice_acceptor
NM_000321.3 splice_acceptor
Scores
3
3
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 6.91
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 16 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.1, offset of 47, new splice context is: aatgatgattttaaattcAGcaa. 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;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 13-48373403-A-G is Pathogenic according to our data. Variant chr13-48373403-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 428715.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1128-2A>G | splice_acceptor_variant | ENST00000267163.6 | |||
LOC112268118 | XR_002957522.2 | n.121+757T>C | intron_variant, non_coding_transcript_variant | ||||
RB1 | NM_001407165.1 | c.1128-2A>G | splice_acceptor_variant | ||||
RB1 | NM_001407166.1 | c.1128-2A>G | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1128-2A>G | splice_acceptor_variant | 1 | NM_000321.3 | P1 | |||
RB1 | ENST00000650461.1 | c.1128-2A>G | splice_acceptor_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 26
GnomAD4 exome
Cov.:
26
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2015 | The c.1128-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 12 in the RB1 gene. This mutation has been reported in an individual diagnosed with familial retinoblastoma (Dommering CJ, et al. J. Med. Genet. 2014 Jun; 51(6):366-74). In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice acceptor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at