rs515726196

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_015713.5(RRM2B):​c.671T>G​(p.Ile224Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

RRM2B
NM_015713.5 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:2

Conservation

PhyloP100: 9.26

Publications

8 publications found
Variant links:
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]
RRM2B Gene-Disease associations (from GenCC):
  • mitochondrial DNA depletion syndrome 8a
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal dominant progressive external ophthalmoplegia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Kearns-Sayre syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • mitochondrial neurogastrointestinal encephalomyopathy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015713.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 8-102218827-A-C is Pathogenic according to our data. Variant chr8-102218827-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RRM2BNM_015713.5 linkc.671T>G p.Ile224Ser missense_variant Exon 6 of 9 ENST00000251810.8 NP_056528.2 Q7LG56-1
RRM2BNM_001172477.1 linkc.887T>G p.Ile296Ser missense_variant Exon 6 of 9 NP_001165948.1 Q7LG56-6
RRM2BNM_001172478.2 linkc.515T>G p.Ile172Ser missense_variant Exon 5 of 8 NP_001165949.1 Q7LG56-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RRM2BENST00000251810.8 linkc.671T>G p.Ile224Ser missense_variant Exon 6 of 9 1 NM_015713.5 ENSP00000251810.3 Q7LG56-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251124
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000240
AC:
35
AN:
1460400
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
AN XY:
726646
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33448
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39686
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86234
European-Finnish (FIN)
AF:
0.0000375
AC:
2
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000288
AC:
32
AN:
1110670
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74258
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41392
American (AMR)
AF:
0.00
AC:
0
AN:
15258
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10572
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000173
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

RRM2B-related mitochondrial disease Pathogenic:1Other:2
Mar 15, 2023
Clinical Genomic Analysis (GENYSIS) Core, University of North Carolina at Chapel Hill
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

RRM2B c.671T>G, p.(Ile224Ser), is a missense variant that changes a single amino acid from a highly conserved isoleucine to a serine. This is a rare variant present at an allele frequency of 0.0026% (4/152,056 alleles) in the gnomADv3.1 population database and reported as pathogenic/likely pathogenic by several clinical laboratories in the ClinVar database. In addition, multiple in silico models predict that the variant has a damaging effect on the protein. The RRM2B c.671T>G variant has previously been reported in an individual with late-onset PEO at 48 years, proximal muscle weakness, cataracts, and migraine (PMID: 23107649). The variant has also been reported as homozygous or in trans with another pathogenic variant in at least two individuals with neonatal-onset autosomal recessive MDMDs (PMID: 18504129, PMID: 30049826). Based on the available information, we consider this variant likely pathogenic. ACMG codes: PM2_Supporting (rare in gnomAD), PM3 (detected in trans with a pathogenic variant), PP3_Strong (REVEL score >= 0.932). -

-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

-
GenomeConnect, ClinGen
Significance:not provided
Review Status:no classification provided
Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 05-12-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Pathogenic:2
Dec 25, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 224 of the RRM2B protein (p.Ile224Ser). This variant is present in population databases (rs515726196, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions and autosomal recessive mitochondrial DNA depletion syndrome (PMID: 18504129, 23107649, 31462754; Invitae). ClinVar contains an entry for this variant (Variation ID: 132122). 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 expected to disrupt RRM2B protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 27, 2025
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30049826, 24741716, 18504129, 23107649) -

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
Apr 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 8a Pathogenic:1
Mar 16, 2018
Centre for Translational Omics - GOSgene, University College London
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 Pathogenic:1
Feb 10, 2025
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

The highest population allele frequency in gnomAD v4.0 is 0.00003127 (0.003%; 2/63966 alleles in the European/Finnish population). PP3_Strong: Revel score is 0.987. PP1 Not Met: 1 informative meiosis in 1 family (clinical testing). PS4_Moderate: 5 unrelated probands with consistent phenotype for disorder (PMID:23107649, PMID:24086434). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D;T;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
H;.;.
PhyloP100
9.3
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.7
D;.;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.98
MVP
1.0
MPC
1.4
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.97
gMVP
0.97
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs515726196; hg19: chr8-103231055; API