NM_015713.5:c.48+273G>T

Variant names:

• chr8-102238554-C-A
• rs149523343
• NM_015713.5:c.48+273G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_015713.5(RRM2B):​c.48+273G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,512,064 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (23 hom.)
• Consequence: RRM2B NM_015713.5 intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.270
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 8-102238554-C-A is Benign according to our data. Variant chr8-102238554-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00848 (1291/152304) while in subpopulation AFR AF = 0.03 (1247/41560). AF 95% confidence interval is 0.0286. There are 15 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015713.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	NM_015713.5	MANE Select	c.48+273G>T		intron	N/A	NP_056528.2
	RRM2B	NM_001172477.1		c.264+5G>T		splice_region intron	N/A	NP_001165948.1
	RRM2B	NM_001172478.2		c.48+273G>T		intron	N/A	NP_001165949.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	ENST00000251810.8	TSL:1 MANE Select	c.48+273G>T		intron	N/A	ENSP00000251810.3
	RRM2B	ENST00000395912.6	TSL:1	c.48+273G>T		intron	N/A	ENSP00000379248.2
	RRM2B	ENST00000519317.5	TSL:1	c.48+273G>T		intron	N/A	ENSP00000430641.1

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1286 AN: 152186 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00179 AC: 237 AN: 132516 AF XY: 0.00155

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.00139

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: 0.00147

GnomAD4 exome AF: 0.000855 AC: 1163 AN: 1359760 Hom.: 23 Cov.: 30 AF XY: 0.000724 AC XY: 485 AN XY: 670228

African (AFR) AF: 0.0314 AC: 974 AN: 31018

American (AMR) AF: 0.00149 AC: 52 AN: 34842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24496

East Asian (EAS) AF: 0.00 AC: 0 AN: 34140

South Asian (SAS) AF: 0.000154 AC: 12 AN: 77982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31518

Middle Eastern (MID) AF: 0.000908 AC: 5 AN: 5506

European-Non Finnish (NFE) AF: 0.0000103 AC: 11 AN: 1063882

Other (OTH) AF: 0.00193 AC: 109 AN: 56376

GnomAD4 genome AF: 0.00848 AC: 1291 AN: 152304 Hom.: 15 Cov.: 33 AF XY: 0.00783 AC XY: 583 AN XY: 74482

African (AFR) AF: 0.0300 AC: 1247 AN: 41560

American (AMR) AF: 0.00196 AC: 30 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00463 Hom.: 1

Bravo AF: 0.00963

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RRM2B-related disorder Benign:1

Mar 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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 Benign:1

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		-0.27
PromoterAI		-0.095	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
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: rs149523343; hg19: chr8-103250782;