chr13-48456349-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000321.3(RB1):c.1960G>A(p.Val654Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V654A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1960G>A | p.Val654Met | missense_variant, splice_region_variant | 19/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1960G>A | p.Val654Met | missense_variant, splice_region_variant | 19/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1960G>A | p.Val654Met | missense_variant, splice_region_variant | 19/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1960G>A | p.Val654Met | missense_variant, splice_region_variant | 19/27 | ||||
RB1 | ENST00000643064.1 | c.194+74906G>A | intron_variant | ||||||
RB1 | ENST00000480491.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, flagged submission | literature only | Richard Lifton Laboratory, Yale University School of Medicine | - | - - |
Likely pathogenic, no assertion criteria provided | literature only | Richard Lifton Laboratory, Yale University School of Medicine | - | - - |
Retinoblastoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 16, 2021 | This variant disrupts the c.1960G nucleotide in the RB1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12541220, 15605413, 18181215, 21615945, 28606269). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 100808). This missense change has been observed in individual(s) with retinoblastoma (PMID: 14722923, 15884040, 22084214, 26925970, 29568217). It has also been observed in individuals without personal history of RB1-related conditions (PMID:29568217, 22084214, 26925970, 14722923). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 654 of the RB1 protein (p.Val654Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant also falls at the last nucleotide of exon 19, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at