rs515726184
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_015713.5(RRM2B):c.253_255del(p.Glu85del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
RRM2B
NM_015713.5 inframe_deletion
NM_015713.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.97
Genes affected
RRM2B (HGNC:17296): (ribonucleotide reductase regulatory TP53 inducible subunit M2B) This gene encodes the small subunit of a p53-inducible ribonucleotide reductase. This heterotetrameric enzyme catalyzes the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. The product of this reaction is necessary for DNA synthesis. Mutations in this gene have been associated with autosomal recessive mitochondrial DNA depletion syndrome, autosomal dominant progressive external ophthalmoplegia-5, and mitochondrial neurogastrointestinal encephalopathy. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
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Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_015713.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
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Variant 8-102225983-TCTC-T is Pathogenic according to our data. Variant chr8-102225983-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132109.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, not_provided=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RRM2B | NM_015713.5 | c.253_255del | p.Glu85del | inframe_deletion | 3/9 | ENST00000251810.8 | |
RRM2B | NM_001172477.1 | c.469_471del | p.Glu157del | inframe_deletion | 3/9 | ||
RRM2B | NM_001172478.2 | c.97_99del | p.Glu33del | inframe_deletion | 2/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RRM2B | ENST00000251810.8 | c.253_255del | p.Glu85del | inframe_deletion | 3/9 | 1 | NM_015713.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251302Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135820
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1460530Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 726636
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2022 | Reported previously in trans with a missense variant in an infant with severe mitochondrial depletion (Bourdon et al., 2007); Reported previously in the heterozygous state in two adults with late-onset progressive external ophthalmoplegia (Pitceathly et al., 2011; Heighton et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 21378381, 17486094, 31521625, 29241262, 33300680) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This variant, c.253_255del, results in the deletion of 1 amino acid(s) of the RRM2B protein (p.Glu85del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs515726184, gnomAD 0.002%). This variant has been observed in individuals with clinical features of autosomal dominant progressive external ophthalmoplegia (PMID: 21378381, 31521625; Invitae). This variant has been reported in individual(s) with autosomal recessive mitochondrial DNA depletion syndrome (PMID: 17486094); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 132109). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction;C2749861:Mitochondrial DNA depletion syndrome 8a;C2751319:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 14, 2021 | - - |
Idiopathic camptocormia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Department of Neurology, University Hospital of Strasbourg | Jan 01, 2013 | - - |
Mitochondrial DNA depletion syndrome 8a Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2007 | - - |
RRM2B-related mitochondrial disease Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at