rs121918311

chr8-102214157-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

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:2 U:1 O:1
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 25) in uniprot entity RIR2B_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_015713.5
• 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: {not_provided=1, Pathogenic=1, Uncertain_significance=1}. Variant chr8-102214157-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRM2B	NM_015713.5	c.686G>T	p.Gly229Val	missense_variant, splice_region_variant	7/9	ENST00000251810.8
RRM2B	NM_001172477.1	c.902G>T	p.Gly301Val	missense_variant, splice_region_variant	7/9
RRM2B	NM_001172478.2	c.530G>T	p.Gly177Val	missense_variant, splice_region_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM2B	ENST00000251810.8	c.686G>T	p.Gly229Val	missense_variant, splice_region_variant	7/9	1	NM_015713.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250936 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135632

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

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.: 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:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 26, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 15, 2023	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. ClinVar contains an entry for this variant (Variation ID: 5392). 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. This variant is present in population databases (rs121918311, gnomAD 0.003%). 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). 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. -

Mitochondrial DNA depletion syndrome 8a Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2009

- -

RRM2B-related mitochondrial disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
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

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

Other links and lift over

dbSNP: rs121918311; hg19: chr8-103226385;