rs770100636
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000321.3(RB1):c.613G>A(p.Val205Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V205V) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.613G>A | p.Val205Ile | missense_variant | 7/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.613G>A | p.Val205Ile | missense_variant | 7/27 | ||
RB1 | NM_001407166.1 | c.613G>A | p.Val205Ile | missense_variant | 7/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.613G>A | p.Val205Ile | missense_variant | 7/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.143G>A | p.Ser48Asn | missense_variant, NMD_transcript_variant | 2/3 | 1 | |||
RB1 | ENST00000650461.1 | c.613G>A | p.Val205Ile | missense_variant | 7/27 | ||||
RB1 | ENST00000525036.1 | n.775G>A | non_coding_transcript_exon_variant | 7/7 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151646Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250068Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135224
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459712Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726242
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151646Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74012
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 410919). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is present in population databases (rs770100636, gnomAD 0.002%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 205 of the RB1 protein (p.Val205Ile). - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at