8-102204606-C-T

Position:

• chr8-102204606-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015713.5(RRM2B):​c.*3527G>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 0.0554 in 151,584 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (258 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: 0.625

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 8-102204606-C-T is Benign according to our data. Variant chr8-102204606-C-T is described in ClinVar as [Benign]. Clinvar id is 361126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRM2B	NM_015713.5	c.*3527G>A		3_prime_UTR_variant	9/9	ENST00000251810.8	NP_056528.2
RRM2B	NM_001172477.1	c.*3527G>A		3_prime_UTR_variant	9/9		NP_001165948.1
RRM2B	NM_001172478.2	c.*3527G>A		3_prime_UTR_variant	8/8		NP_001165949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRM2B	ENST00000251810	c.*3527G>A		3_prime_UTR_variant	9/9	1	NM_015713.5	ENSP00000251810.3

Frequencies

GnomAD3 genomes AF: 0.0554 AC: 8392 AN: 151466 Hom.: 258 Cov.: 32

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0857

Gnomad EAS AF: 0.0282

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.0700

Gnomad OTH AF: 0.0582

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

GnomAD4 genome AF: 0.0554 AC: 8397 AN: 151584 Hom.: 258 Cov.: 32 AF XY: 0.0537 AC XY: 3980 AN XY: 74054

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.0434

Gnomad4 ASJ AF: 0.0857

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.0227

Gnomad4 FIN AF: 0.0634

Gnomad4 NFE AF: 0.0701

Gnomad4 OTH AF: 0.0576

Alfa AF: 0.0639 Hom.: 163

Bravo AF: 0.0550

Asia WGS AF: 0.0340 AC: 117 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 8a Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.6
DANN	Benign	0.48

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

LitVar

Other links and lift over

dbSNP: rs1052071; hg19: chr8-103216834;