NM_001033.5:c.361T>C

Variant names:

• chr11-4107509-T-C
• rs2228121
• NM_001033.5:c.361T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001033.5(RRM1):​c.361T>C​(p.Leu121Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,613,050 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (31 hom.)
• Consequence: RRM1 NM_001033.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16
• Publications: 2 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, autosomal recessive 6

  Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, G2P
• progressive external ophthalmoplegia with mitochondrial DNA deletions

  Inheritance: AD, AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-4107509-T-C is Benign according to our data. Variant chr11-4107509-T-C is described in ClinVar as Benign. ClinVar VariationId is 731616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1548/152328) while in subpopulation AFR AF = 0.0322 (1337/41572). AF 95% confidence interval is 0.0307. There are 15 homozygotes in GnomAd4. There are 759 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033.5. 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
	RRM1	NM_001033.5	MANE Select	c.361T>C	p.Leu121Leu	synonymous	Exon 4 of 19	NP_001024.1	P23921
	RRM1	NM_001318064.1		c.70T>C	p.Leu24Leu	synonymous	Exon 3 of 18	NP_001304993.1	B4E0I8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM1	ENST00000300738.10	TSL:1 MANE Select	c.361T>C	p.Leu121Leu	synonymous	Exon 4 of 19	ENSP00000300738.5	P23921
	RRM1	ENST00000854928.1		c.361T>C	p.Leu121Leu	synonymous	Exon 4 of 19	ENSP00000524987.1
	RRM1	ENST00000854929.1		c.361T>C	p.Leu121Leu	synonymous	Exon 4 of 18	ENSP00000524988.1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1545 AN: 152210 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00372 AC: 934 AN: 251368 AF XY: 0.00305

Gnomad AFR exome AF: 0.0321

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00176 AC: 2573 AN: 1460722 Hom.: 31 Cov.: 29 AF XY: 0.00157 AC XY: 1140 AN XY: 726740

African (AFR) AF: 0.0343 AC: 1148 AN: 33428

American (AMR) AF: 0.00340 AC: 152 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 596 AN: 26118

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39648

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86234

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53406

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5756

European-Non Finnish (NFE) AF: 0.000360 AC: 400 AN: 1111054

Other (OTH) AF: 0.00396 AC: 239 AN: 60356

GnomAD4 genome AF: 0.0102 AC: 1548 AN: 152328 Hom.: 15 Cov.: 33 AF XY: 0.0102 AC XY: 759 AN XY: 74504

African (AFR) AF: 0.0322 AC: 1337 AN: 41572

American (AMR) AF: 0.00575 AC: 88 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68024

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00596 Hom.: 7

Bravo AF: 0.0118

Asia WGS AF: 0.00202 AC: 8 AN: 3476

EpiCase AF: 0.00120

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.6
DANN	Benign	0.76
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs2228121; hg19: chr11-4128739;