11-4095925-T-C

Variant names:

• chr11-4095925-T-C
• rs1662172
• NM_001033.5:c.19+894T>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.19+894T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 152,076 control chromosomes in the GnomAD database, including 20,927 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 0.52 (20927 hom., cov: 32)
• Consequence: RRM1 NM_001033.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• Publications: 11 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM1	NM_001033.5	c.19+894T>C		intron_variant	Intron 1 of 18	ENST00000300738.10	NP_001024.1
RRM1	NM_001318064.1	c.-95+894T>C		intron_variant	Intron 1 of 17		NP_001304993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM1	ENST00000300738.10	c.19+894T>C		intron_variant	Intron 1 of 18	1	NM_001033.5	ENSP00000300738.5

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78840 AN: 151960 Hom.: 20930 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.532

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

GnomAD4 genome AF: 0.519 AC: 78853 AN: 152076 Hom.: 20927 Cov.: 32 AF XY: 0.512 AC XY: 38056 AN XY: 74348

African (AFR) AF: 0.409 AC: 16977 AN: 41474

American (AMR) AF: 0.527 AC: 8059 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1875 AN: 3470

East Asian (EAS) AF: 0.480 AC: 2480 AN: 5170

South Asian (SAS) AF: 0.480 AC: 2312 AN: 4820

European-Finnish (FIN) AF: 0.499 AC: 5272 AN: 10574

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.589 AC: 40052 AN: 67980

Other (OTH) AF: 0.530 AC: 1115 AN: 2104

Alfa AF: 0.565 Hom.: 78423

Bravo AF: 0.518

Asia WGS AF: 0.464 AC: 1612 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		0.25
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: rs1662172; hg19: chr11-4117155;