rs769113950
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000321.3(RB1):c.1961T>A(p.Val654Glu) variant causes a missense, splice region 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). 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
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1961T>A | p.Val654Glu | missense_variant, splice_region_variant | 20/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1961T>A | p.Val654Glu | missense_variant, splice_region_variant | 20/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1961T>A | p.Val654Glu | missense_variant, splice_region_variant | 20/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1961T>A | p.Val654Glu | missense_variant, splice_region_variant | 20/27 | ||||
RB1 | ENST00000643064.1 | c.194+78245T>A | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 27, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with bilateral retinoblastomas (PMID: 7795591). ClinVar contains an entry for this variant (Variation ID: 978459). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with glutamic acid at codon 654 of the RB1 protein (p.Val654Glu). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glutamic acid. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | May 09, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at