rs121918311

Variant names:

• chr8-102214157-C-A
• rs121918311
• NM_015713.5:c.686G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B.

Score: 4 - Uncertain Significance

4

PM1PP3PP5

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. 14/24 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:3 U:1 O:1
• Conservation: PhyloP100: 7.86
• Publications: 12 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_015713.5
• PP3: Splicing predictors support a deleterious 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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250936 AF XY: 0.0000147

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1452524 Hom.: 0 Cov.: 27 AF XY: 0.0000138 AC XY: 10 AN XY: 723326

African (AFR) AF: 0.00 AC: 0 AN: 33236

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1103940

Other (OTH) AF: 0.00 AC: 0 AN: 60030

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000446 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain: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	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.4	H;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
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	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.84
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918311; hg19: chr8-103226385;