rs515726184

Positions:

chr8-102225983-TCTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5

The NM_015713.5(RRM2B):c.253_255del(p.Glu85del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RRM2B
NM_015713.5 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:1

Conservation

PhyloP100: 7.97

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_015713.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 8-102225983-TCTC-T is Pathogenic according to our data. Variant chr8-102225983-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132109.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RRM2B	NM_015713.5 linkuse as main transcript	c.253_255del	p.Glu85del	inframe_deletion	3/9	ENST00000251810.8
RRM2B	NM_001172477.1 linkuse as main transcript	c.469_471del	p.Glu157del	inframe_deletion	3/9
RRM2B	NM_001172478.2 linkuse as main transcript	c.97_99del	p.Glu33del	inframe_deletion	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM2B	ENST00000251810.8 linkuse as main transcript	c.253_255del	p.Glu85del	inframe_deletion	3/9	1	NM_015713.5	P1	Q7LG56-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251302

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135820

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1460530

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

726636

show subpopulations

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:

0.0000216

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2022	Reported previously in trans with a missense variant in an infant with severe mitochondrial depletion (Bourdon et al., 2007); Reported previously in the heterozygous state in two adults with late-onset progressive external ophthalmoplegia (Pitceathly et al., 2011; Heighton et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 21378381, 17486094, 31521625, 29241262, 33300680) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This variant, c.253_255del, results in the deletion of 1 amino acid(s) of the RRM2B protein (p.Glu85del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs515726184, gnomAD 0.002%). This variant has been observed in individuals with clinical features of autosomal dominant progressive external ophthalmoplegia (PMID: 21378381, 31521625; Invitae). This variant has been reported in individual(s) with autosomal recessive mitochondrial DNA depletion syndrome (PMID: 17486094); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 132109). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction;C2749861:Mitochondrial DNA depletion syndrome 8a;C2751319:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 14, 2021

- -

Idiopathic camptocormia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Department of Neurology, University Hospital of Strasbourg

Jan 01, 2013

- -

Mitochondrial DNA depletion syndrome 8a

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

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

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over