13-48465008-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_000321.3(RB1):c.2222G>A(p.Arg741His) variant causes a missense change. The variant allele was found at a frequency of 0.0000259 in 1,118,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. R741C) 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.2222G>A | p.Arg741His | missense_variant | 22/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.2222G>A | p.Arg741His | missense_variant | 22/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.2222G>A | p.Arg741His | missense_variant | 22/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.2222G>A | p.Arg741His | missense_variant | 22/27 | ||||
RB1 | ENST00000643064.1 | c.194+83565G>A | intron_variant |
Frequencies
GnomAD3 genomes AF: 0.0000179 AC: 2AN: 111640Hom.: 0 Cov.: 24
GnomAD3 exomes AF: 0.0000204 AC: 5AN: 245098Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132652
GnomAD4 exome AF: 0.0000268 AC: 27AN: 1007328Hom.: 0 Cov.: 34 AF XY: 0.0000254 AC XY: 13AN XY: 511232
GnomAD4 genome AF: 0.0000179 AC: 2AN: 111640Hom.: 0 Cov.: 24 AF XY: 0.0000393 AC XY: 2AN XY: 50844
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2023 | The p.R741H variant (also known as c.2222G>A), located in coding exon 22 of the RB1 gene, results from a G to A substitution at nucleotide position 2222. The arginine at codon 741 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Retinoblastoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at