rs2268166

Variant names:

• chr11-4104779-T-G
• rs2268166
• NM_001033.5:c.109-1267T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001033.5(RRM1):​c.109-1267T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 152,216 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.056 (251 hom., cov: 32)
• Consequence: RRM1 NM_001033.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980
• Publications: 6 publications found

Genes affected

RRM1 (HGNC:10451): (ribonucleotide reductase catalytic subunit M1) This gene encodes the large and catalytic subunit of ribonucleotide reductase, an enzyme essential for the conversion of ribonucleotides into deoxyribonucleotides. A pool of available deoxyribonucleotides is important for DNA replication during S phase of the cell cycle as well as multiple DNA repair processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

RRM1 Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics
• progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

  Inheritance: AR, AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM1	NM_001033.5	c.109-1267T>G		intron_variant	Intron 2 of 18	ENST00000300738.10	NP_001024.1
RRM1	NM_001318064.1	c.-5-2656T>G		intron_variant	Intron 2 of 17		NP_001304993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM1	ENST00000300738.10	c.109-1267T>G		intron_variant	Intron 2 of 18	1	NM_001033.5	ENSP00000300738.5

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8463 AN: 152100 Hom.: 252 Cov.: 32

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0722

Gnomad SAS AF: 0.0810

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0489

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0557 AC: 8471 AN: 152216 Hom.: 251 Cov.: 32 AF XY: 0.0557 AC XY: 4148 AN XY: 74438

African (AFR) AF: 0.0865 AC: 3587 AN: 41486

American (AMR) AF: 0.0470 AC: 720 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.0724 AC: 375 AN: 5182

South Asian (SAS) AF: 0.0800 AC: 386 AN: 4826

European-Finnish (FIN) AF: 0.0247 AC: 262 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2943 AN: 68020

Other (OTH) AF: 0.0493 AC: 104 AN: 2108

Alfa AF: 0.0466 Hom.: 217

Bravo AF: 0.0571

Asia WGS AF: 0.0860 AC: 299 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.098
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: rs2268166; hg19: chr11-4126009;