rs863224193

chr8-102218836-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_015713.5(RRM2B):c.662A>G(p.Asn221Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RRM2B NM_015713.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.96

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 9 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: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 8-102218836-T-C is Pathogenic according to our data. Variant chr8-102218836-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215094.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRM2B	NM_015713.5	c.662A>G	p.Asn221Ser	missense_variant	6/9	ENST00000251810.8
RRM2B	NM_001172477.1	c.878A>G	p.Asn293Ser	missense_variant	6/9
RRM2B	NM_001172478.2	c.506A>G	p.Asn169Ser	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM2B	ENST00000251810.8	c.662A>G	p.Asn221Ser	missense_variant	6/9	1	NM_015713.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251170 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461376 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial DNA depletion syndrome 8a Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 29, 2020	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2015

p.Asn221Ser (AAT>AGT):c.662 A>G in exon 6 of the RRM2B gene (NM_015713.4). The N221S missense change in the RRM2B gene is likely disease-causing. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is conservative in that both Asparagine and Serine are uncharged, polar amino acids; however, this change occurs at a highly conserved position in the RRM2B protein, and other missense mutations at neighboring positions (I224S, G229V) have been reported in association with mitochondrial DNA depletion syndrome. Furthermore, multiple in-silico analysis models predict that N221S is damaging to the RRM2B protein. Therefore, N221S is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. Mutations in the RRM2B gene are associated with the autosomal recessive condition, mitochondrial DNA depletion syndrome 8A (MTDPS8A) and with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 5 (PEOA5). Autosomal dominant disease-causing mutations are typically associated with adult-onset of symptoms. The variant is found in MITONUC-MITOP panel(s). -

Severe lactic acidosis Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Pediatric Genomics Discovery Program, Yale University

Jul 13, 2017

We identified a homozygous p.Asn221Ser variant in RRM2B in an infant who developed hypotonia, failure to thrive, sensorineural hearing loss, and severe metabolic lactic acidosis, ultimately progressing to death at 3 months of age. Tissue studies to confirm the diagnosis of mitochondrial depletion were unable to be performed. Through molecular modeling using the X-ray crystal structure of p53R2, this variant likely causes disruption of a highly conserved helix region of the protein by altering intramolecular interactions (Smith et al. 2009; Scrutton and Raine 1996; Burley and Petsko 1986; Mitchell et al. 1994). Using ACMG 2015 Classification guidelines, this variant falls within VUS classification; however, there are now two unrelated homozygous patients (including this patient) reported with apparently similar presentations in ClinVar. This variant has been reported twice in ClinVar previously: once by Baylor Miraca Genetics Laboratory (SCV000807524.1) and once by GeneDx (SCV000252199.13). The patient described in SCV000807524.1 was 4 mo old and had renal tubular acidosis and congenital glaucoma, as well as a phenotype overlapping the patient described in this submission; this patient was also homozygous. The diagnosis Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) was associated with SCV000807524.1. No clinical information was provided for SCV000252199.13. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.9	D;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.84
MutPred		0.90		Gain of disorder (P = 0.0401);.;.;
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs863224193; hg19: chr8-103231064;