rs772678500
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000321.3(RB1):c.752G>A(p.Arg251Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,592 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. R251G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.752G>A | p.Arg251Gln | missense_variant | 8/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.752G>A | p.Arg251Gln | missense_variant | 8/27 | ||
RB1 | NM_001407166.1 | c.752G>A | p.Arg251Gln | missense_variant | 8/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.752G>A | p.Arg251Gln | missense_variant | 8/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.*120G>A | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 1 | ||||
RB1 | ENST00000650461.1 | c.752G>A | p.Arg251Gln | missense_variant | 8/27 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251134Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135718
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461554Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727102
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74236
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 | Jun 08, 2023 | This missense variant replaces arginine with glutamine at codon 251 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/251134 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 10, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2022 | The p.R251Q variant (also known as c.752G>A), located in coding exon 8 of the RB1 gene, results from a G to A substitution at nucleotide position 752. The arginine at codon 251 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Malignant tumor of urinary bladder;C0035335:Retinoblastoma;C0149925:Small cell lung carcinoma;C0585442:Bone osteosarcoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at