rs121918311

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_015713.5(RRM2B):c.686G>T(p.Gly229Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,452,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

RRM2B
NM_015713.5 missense, splice_region

Scores

Splicing: ADA: 0.9716

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O:1

Conservation

PhyloP100: 7.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 8-102214157-C-A is Pathogenic according to our data. Variant chr8-102214157-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5392.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1, not_provided=1}. Variant chr8-102214157-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2B	NM_015713.5 link	c.686G>T	p.Gly229Val	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000251810.8	NP_056528.2	Q7LG56-1
RRM2B	NM_001172477.1 link	c.902G>T	p.Gly301Val	missense_variant, splice_region_variant	Exon 7 of 9		NP_001165948.1	Q7LG56-6
RRM2B	NM_001172478.2 link	c.530G>T	p.Gly177Val	missense_variant, splice_region_variant	Exon 6 of 8		NP_001165949.1	Q7LG56-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8 link	c.686G>T	p.Gly229Val	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_015713.5	ENSP00000251810.3		Q7LG56-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250936

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135632

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1452524

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

723326

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000154

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000446

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs121918311, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of RRM2B-related conditions (PMID: 19138848, 21646632, 27290639, 33300680). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5392). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 229 of the RRM2B protein (p.Gly229Val). -

May 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PP3, PM3_strong, PS4_moderate -

Jan 26, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RRM2B gene demonstrated a sequence change, c.686G>T, in exon 7 that results in an amino acid change, p.Gly229Val. This sequence change has been previously reported in a homozygous state in two siblings with severe muscular hypotonia, seizures, poor visual contact, feeding difficulties, failure to thrive, lactic acidosis and proximal renal tubulopathy in one sibling (PMID: 19138848). Each unaffected parent was heterozygous for the change. Southern blot analysis of patient's muscle tissue showed severe mtDNA depletion, about 1 to 4% of normal controls. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.0016% (dbSNP rs121918311); however it has not been observed in the homozygous state in any individuals. The p.Gly229Val change affects a highly conserved amino acid residue located in a diferric iron center of the ribonucleotide reductase or RRM2B protein that is known to be functional. The p.Gly229Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic. -

Mitochondrial DNA depletion syndrome 8a

Pathogenic:1

Feb 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

RRM2B-related mitochondrial disease

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;T;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.4

H;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.9

D;.;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.95

MutPred

0.92

Loss of disorder (P = 0.0603);.;.;.;

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over