rs551747882
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_000321.3(RB1):c.2003G>A(p.Arg668His) variant causes a missense change. The variant allele was found at a frequency of 0.0000644 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. R668C) has been classified as Likely benign.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.2003G>A | p.Arg668His | missense_variant | 20/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.2003G>A | p.Arg668His | missense_variant | 20/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.2003G>A | p.Arg668His | missense_variant | 20/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.2003G>A | p.Arg668His | missense_variant | 20/27 | ||||
RB1 | ENST00000643064.1 | c.194+78287G>A | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000527 AC: 8AN: 151888Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251490Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135922
GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461820Hom.: 0 Cov.: 34 AF XY: 0.0000495 AC XY: 36AN XY: 727214
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152004Hom.: 0 Cov.: 30 AF XY: 0.0000673 AC XY: 5AN XY: 74298
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2023 | See Variant Classification Assertion Criteria. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 02, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at