chr8-102204738-G-C

Variant names:

• chr8-102204738-G-C
• rs11575866
• NM_015713.5:c.*3395C>G

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.*3395C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 151,952 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (284 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: -0.172
• Publications: 6 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=-0.91).
• BP6: Variant 8-102204738-G-C is Benign according to our data. Variant chr8-102204738-G-C is described in ClinVar as Benign. ClinVar VariationId is 361129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.091 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.*3395C>G		3_prime_UTR	Exon 9 of 9	NP_056528.2
	RRM2B	NM_001172477.1		c.*3395C>G		3_prime_UTR	Exon 9 of 9	NP_001165948.1	Q7LG56-6
	RRM2B	NM_001172478.2		c.*3395C>G		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.*3395C>G		3_prime_UTR	Exon 9 of 9	ENSP00000251810.3	Q7LG56-1
	RRM2B	ENST00000930763.1		c.*3395C>G		3_prime_UTR	Exon 9 of 9	ENSP00000600822.1
	RRM2B	ENST00000941786.1		c.*3395C>G		3_prime_UTR	Exon 7 of 7	ENSP00000611845.1

Frequencies

GnomAD3 genomes AF: 0.0502 AC: 7618 AN: 151834 Hom.: 284 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0951

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0838

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0547

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: 0.0501 AC: 7607 AN: 151952 Hom.: 284 Cov.: 32 AF XY: 0.0504 AC XY: 3744 AN XY: 74270

African (AFR) AF: 0.0136 AC: 563 AN: 41436

American (AMR) AF: 0.0951 AC: 1451 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0826 AC: 397 AN: 4806

European-Finnish (FIN) AF: 0.0490 AC: 516 AN: 10540

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0655 AC: 4447 AN: 67944

Other (OTH) AF: 0.0532 AC: 112 AN: 2106

Alfa AF: 0.0540 Hom.: 28

Bravo AF: 0.0513

Asia WGS AF: 0.0270 AC: 94 AN: 3472

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	-0.91
CADD	Benign	0.48
DANN	Benign	0.48
PhyloP100		-0.17
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: rs11575866; hg19: chr8-103216966;