NM_001033.5:c.388C>G

Variant names:

• chr11-4109644-C-G
• rs753295405
• NM_001033.5:c.388C>G

Variant summary

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

The NM_001033.5(RRM1):​c.388C>G​(p.Arg130Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R130C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRM1 NM_001033.5 missense, splice_region
• Scores: Splicing: ADA: 0.9421
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.72
• Publications: 0 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.388C>G	p.Arg130Gly	missense splice_region	Exon 5 of 19	NP_001024.1	P23921
	RRM1	NM_001318064.1		c.97C>G	p.Arg33Gly	missense splice_region	Exon 4 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.388C>G	p.Arg130Gly	missense splice_region	Exon 5 of 19	ENSP00000300738.5	P23921
	RRM1	ENST00000854928.1		c.388C>G	p.Arg130Gly	missense splice_region	Exon 5 of 19	ENSP00000524987.1
	RRM1	ENST00000854929.1		c.388C>G	p.Arg130Gly	missense splice_region	Exon 5 of 18	ENSP00000524988.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Benign	0.037	D
Sift4G	Benign	0.24	T
Polyphen		0.95	P
Vest4		0.72
MutPred		0.56		Loss of solvent accessibility (P = 0.0769)
MVP		0.58
MPC		1.4
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.57
gMVP		0.92
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.62
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: rs753295405; hg19: chr11-4130874;