11-4102882-T-C

Variant names:

• chr11-4102882-T-C
• rs1474500
• NM_001033.5:c.108+801T>C

Variant summary

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

The NM_001033.5(RRM1):​c.108+801T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.879 in 152,188 control chromosomes in the GnomAD database, including 59,085 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 0.88 (59085 hom., cov: 32)
• Consequence: RRM1 NM_001033.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM1	NM_001033.5	c.108+801T>C		intron_variant	Intron 2 of 18	ENST00000300738.10	NP_001024.1
RRM1	NM_001318064.1	c.-6+801T>C		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.108+801T>C		intron_variant	Intron 2 of 18	1	NM_001033.5	ENSP00000300738.5

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133710 AN: 152070 Hom.: 59086 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.853

Gnomad ASJ AF: 0.916

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.878

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

GnomAD4 genome AF: 0.879 AC: 133744 AN: 152188 Hom.: 59085 Cov.: 32 AF XY: 0.874 AC XY: 65060 AN XY: 74414

African (AFR) AF: 0.807 AC: 33484 AN: 41484

American (AMR) AF: 0.853 AC: 13047 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 3179 AN: 3472

East Asian (EAS) AF: 0.757 AC: 3928 AN: 5186

South Asian (SAS) AF: 0.934 AC: 4498 AN: 4816

European-Finnish (FIN) AF: 0.887 AC: 9399 AN: 10594

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63388 AN: 68026

Other (OTH) AF: 0.870 AC: 1836 AN: 2110

Alfa AF: 0.918 Hom.: 33134

Bravo AF: 0.869

Asia WGS AF: 0.791 AC: 2753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.3
DANN	Benign	0.47
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1474500; hg19: chr11-4124112;