11-4129128-G-C

Variant names:

• chr11-4129128-G-C
• rs201133430
• NM_001033.5:c.1747G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001033.5(RRM1):​c.1747G>C​(p.Val583Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V583F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RRM1 NM_001033.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1747G>C	p.Val583Leu	missense	Exon 15 of 19	NP_001024.1	P23921
	RRM1	NM_001318064.1		c.1456G>C	p.Val486Leu	missense	Exon 14 of 18	NP_001304993.1	B4E0I8
	RRM1	NM_001330193.1		c.1081G>C	p.Val361Leu	missense	Exon 9 of 13	NP_001317122.1	E9PL69

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM1	ENST00000300738.10	TSL:1 MANE Select	c.1747G>C	p.Val583Leu	missense	Exon 15 of 19	ENSP00000300738.5	P23921
	RRM1	ENST00000854928.1		c.1678G>C	p.Val560Leu	missense	Exon 15 of 19	ENSP00000524987.1
	RRM1	ENST00000854929.1		c.1525G>C	p.Val509Leu	missense	Exon 14 of 18	ENSP00000524988.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249256 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453094 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 723468

African (AFR) AF: 0.00 AC: 0 AN: 33186

American (AMR) AF: 0.00 AC: 0 AN: 44032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105622

Other (OTH) AF: 0.00 AC: 0 AN: 60048

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.45	N
PhyloP100		2.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.039
Sift	Benign	0.32	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.46		Loss of methylation at K582 (P = 0.0575)
MVP		0.11
MPC		0.64
ClinPred		0.037	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.086
gMVP		0.52
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201133430; hg19: chr11-4150358;