rs515726183

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_015713.5(RRM2B):c.208G>T(p.Asp70Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D70N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RRM2B
NM_015713.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.86

Publications

2 publications found

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 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

RRM2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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, 2 uncertain in NM_015713.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 8-102226031-C-A is Pathogenic according to our data. Variant chr8-102226031-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 215100.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RRM2B	NM_015713.5 link	c.208G>T	p.Asp70Tyr	missense_variant	Exon 3 of 9	ENST00000251810.8	NP_056528.2
RRM2B	NM_001172477.1 link	c.424G>T	p.Asp142Tyr	missense_variant	Exon 3 of 9		NP_001165948.1
RRM2B	NM_001172478.2 link	c.52G>T	p.Asp18Tyr	missense_variant	Exon 2 of 8		NP_001165949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810.8 link	c.208G>T	p.Asp70Tyr	missense_variant	Exon 3 of 9	1	NM_015713.5	ENSP00000251810.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1437618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716702

African (AFR)

AF:

0.00

AC:

AN:

32980

American (AMR)

AF:

0.00

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

85742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090262

Other (OTH)

AF:

0.00

AC:

AN:

59584

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

May 07, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30919572) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;T;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

4.4

H;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-8.6

D;.;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.93

MutPred

0.74

Loss of disorder (P = 0.0267);.;.;

MVP

0.98

MPC

1.3

ClinPred

1.0

GERP RS

5.0

Varity_R

0.98

gMVP

0.96

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over