rs200674097
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000321.3(RB1):c.761G>A(p.Arg254Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R254G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.761G>A | p.Arg254Lys | missense_variant | 8/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.761G>A | p.Arg254Lys | missense_variant | 8/27 | ||
RB1 | NM_001407166.1 | c.761G>A | p.Arg254Lys | missense_variant | 8/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.761G>A | p.Arg254Lys | missense_variant | 8/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.*129G>A | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 1 | ||||
RB1 | ENST00000650461.1 | c.761G>A | p.Arg254Lys | missense_variant | 8/27 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251158Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135730
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461594Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727112
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with lysine at codon 254 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has been identified in 3/282558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2023 | This alteration is classified as likely 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 24, 2022 | - - |
Malignant tumor of urinary bladder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 14, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at