NM_015713.5:c.*3593G>A

Variant names:

• chr8-102204540-C-T
• rs29000294
• NM_015713.5:c.*3593G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015713.5(RRM2B):​c.*3593G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0654 in 151,962 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (327 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: RRM2B NM_015713.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0380
• Publications: 5 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: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-102204540-C-T is Benign according to our data. Variant chr8-102204540-C-T is described in ClinVar as Benign. ClinVar VariationId is 361124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.069 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	NM_015713.5	MANE Select	c.*3593G>A		3_prime_UTR	Exon 9 of 9	NP_056528.2
	RRM2B	NM_001172477.1		c.*3593G>A		3_prime_UTR	Exon 9 of 9	NP_001165948.1	Q7LG56-6
	RRM2B	NM_001172478.2		c.*3593G>A		3_prime_UTR	Exon 8 of 8	NP_001165949.1	Q7LG56-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM2B	ENST00000251810.8	TSL:1 MANE Select	c.*3593G>A		3_prime_UTR	Exon 9 of 9	ENSP00000251810.3	Q7LG56-1
	RRM2B	ENST00000930763.1		c.*3593G>A		3_prime_UTR	Exon 9 of 9	ENSP00000600822.1
	RRM2B	ENST00000941786.1		c.*3593G>A		downstream_gene	N/A	ENSP00000611845.1

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9931 AN: 151844 Hom.: 327 Cov.: 32

Gnomad AFR AF: 0.0712

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0501

Gnomad ASJ AF: 0.0856

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0699

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0654 AC: 9941 AN: 151962 Hom.: 327 Cov.: 32 AF XY: 0.0640 AC XY: 4750 AN XY: 74266

African (AFR) AF: 0.0712 AC: 2950 AN: 41442

American (AMR) AF: 0.0500 AC: 763 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 297 AN: 3468

East Asian (EAS) AF: 0.0286 AC: 148 AN: 5172

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4818

European-Finnish (FIN) AF: 0.0633 AC: 667 AN: 10544

Middle Eastern (MID) AF: 0.131 AC: 38 AN: 290

European-Non Finnish (NFE) AF: 0.0702 AC: 4772 AN: 67948

Other (OTH) AF: 0.0691 AC: 146 AN: 2112

Alfa AF: 0.0682 Hom.: 80

Bravo AF: 0.0666

Asia WGS AF: 0.0370 AC: 128 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mitochondrial DNA depletion syndrome 8a (1)
-	-	1	not provided (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.65
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism (auto)

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: rs29000294; hg19: chr8-103216768;