rs1131690895
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong
The NM_000321.3(RB1):c.607+2dup variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
RB1
NM_000321.3 splice_donor
NM_000321.3 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.05
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 14 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.024040187 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 0 (no position change), new splice context is: aagGTtaag. Cryptic site results in inframe 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: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 13-48349024-G-GT is Pathogenic according to our data. Variant chr13-48349024-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.607+2dup | splice_donor_variant | ENST00000267163.6 | |||
RB1 | NM_001407165.1 | c.607+2dup | splice_donor_variant | ||||
RB1 | NM_001407166.1 | c.607+2dup | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.607+2dup | splice_donor_variant | 1 | NM_000321.3 | P1 | |||
RB1 | ENST00000467505.5 | c.138-10992dup | intron_variant, NMD_transcript_variant | 1 | |||||
RB1 | ENST00000650461.1 | c.607+2dup | splice_donor_variant | ||||||
RB1 | ENST00000525036.1 | n.769+2dup | splice_donor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1442952Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1AN XY: 717874
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinoblastoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2019 | This variant has been observed to be de novo in an individual affected with retinoblastoma (Invitae). ClinVar contains an entry for this variant (Variation ID: 428720). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 6 of the RB1 gene. It does not directly change the encoded amino acid sequence of the RB1 protein, but it affects a nucleotide within the consensus splice site of the intron. For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2015 | The c.607+2dupT intronic variant, results from a duplication of the T, 2 nucleotides after exon 6 of the RB1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6470 samples (12940 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.21% (greater than 475 alleles tested) in our clinical cohort. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to significantly reduce the native splice donor site efficiency; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at