rs863224193

Variant names:

• chr8-102218836-T-C
• rs863224193
• NM_015713.5:c.662A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 3 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: Likely_pathogenic. The variant received 9 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, 3 uncertain 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 VariationId is 215094.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM2B	NM_015713.5	c.662A>G	p.Asn221Ser	missense_variant	Exon 6 of 9	ENST00000251810.8	NP_056528.2
RRM2B	NM_001172477.1	c.878A>G	p.Asn293Ser	missense_variant	Exon 6 of 9		NP_001165948.1
RRM2B	NM_001172478.2	c.506A>G	p.Asn169Ser	missense_variant	Exon 5 of 8		NP_001165949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8	c.662A>G	p.Asn221Ser	missense_variant	Exon 6 of 9	1	NM_015713.5	ENSP00000251810.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251170 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111566

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

May 18, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 13, 2017

Pediatric Genomics Discovery Program, Yale University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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;.;.
PhyloP100		8.0
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863224193; hg19: chr8-103231064;