rs387906892
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_015713.5(RRM2B):c.97C>T(p.Pro33Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_015713.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RRM2B | NM_015713.5 | c.97C>T | p.Pro33Ser | missense_variant | 2/9 | ENST00000251810.8 | |
RRM2B | NM_001172477.1 | c.313C>T | p.Pro105Ser | missense_variant | 2/9 | ||
RRM2B | NM_001172478.2 | c.49-6222C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RRM2B | ENST00000251810.8 | c.97C>T | p.Pro33Ser | missense_variant | 2/9 | 1 | NM_015713.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251478Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461736Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727190
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Mitochondrial DNA depletion syndrome 8a Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86). The variant has been previously reported to be associated with RRM2B-related disorder (ClinVar ID: VCV000030436 / PMID: 21951382). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2021 | This sequence change replaces proline with serine at codon 33 of the RRM2B protein (p.Pro33Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs387906892, ExAC 0.01%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 21951382). ClinVar contains an entry for this variant (Variation ID: 30436). - |
Progressive external ophthalmoplegia Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Sep 28, 2011 | - - |
RRM2B-related mitochondrial disease Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at