rs367578442
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2
The NM_000321.3(RB1):c.1861C>A(p.Arg621Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R621C) has been classified as Likely benign.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1861C>A | p.Arg621Ser | missense_variant | 19/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1861C>A | p.Arg621Ser | missense_variant | 19/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1861C>A | p.Arg621Ser | missense_variant | 19/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1861C>A | p.Arg621Ser | missense_variant | 19/27 | ||||
RB1 | ENST00000643064.1 | c.194+74807C>A | intron_variant | ||||||
RB1 | ENST00000480491.1 | n.560C>A | non_coding_transcript_exon_variant | 3/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251442Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135902
GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727230
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74452
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 14, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 29, 2021 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2018 | This variant is associated with the following publications: (PMID: 24728327, 24791139, 29192238) - |
RB1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 26, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at