rs896487590
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000321.3(RB1):āc.109A>Cā(p.Ser37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,315,728 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 Uncertain significance (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S37G) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.109A>C | p.Ser37Arg | missense_variant | 1/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.109A>C | p.Ser37Arg | missense_variant | 1/27 | ||
RB1 | NM_001407166.1 | c.109A>C | p.Ser37Arg | missense_variant | 1/17 | ||
RB1 | NM_001407167.1 | c.109A>C | p.Ser37Arg | missense_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.109A>C | p.Ser37Arg | missense_variant | 1/27 | 1 | NM_000321.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000152 AC: 2AN: 1315728Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 648602
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 527902). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 37 of the RB1 protein (p.Ser37Arg). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2020 | The p.S37R variant (also known as c.109A>C), located in coding exon 1 of the RB1 gene, results from an A to C substitution at nucleotide position 109. The serine at codon 37 is replaced by arginine, an amino acid with dissimilar 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at