NM_001033.5:c.1142G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001033.5(RRM1):​c.1142G>A​(p.Arg381His) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RRM1
NM_001033.5 missense

Scores

3
7
9

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-4123206-G-A is Pathogenic according to our data. Variant chr11-4123206-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2444243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RRM1NM_001033.5 linkc.1142G>A p.Arg381His missense_variant Exon 12 of 19 ENST00000300738.10 NP_001024.1 P23921
RRM1NM_001318064.1 linkc.851G>A p.Arg284His missense_variant Exon 11 of 18 NP_001304993.1 P23921B4E0I8
RRM1NM_001330193.1 linkc.476G>A p.Arg159His missense_variant Exon 6 of 13 NP_001317122.1 E9PL69
RRM1NM_001318065.1 linkc.128G>A p.Arg43His missense_variant Exon 6 of 13 NP_001304994.1 P23921B4DXD1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RRM1ENST00000300738.10 linkc.1142G>A p.Arg381His missense_variant Exon 12 of 19 1 NM_001033.5 ENSP00000300738.5 P23921

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151994
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461774
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151994
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74236
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6 Pathogenic:2
Dec 07, 2023
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dec 19, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

RRM1-related disorder Pathogenic:1
Jan 19, 2025
3billion, Medical Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.26; 3Cnet: 0.01). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV002444243 / PMID: 35617047). A different missense change at the same codon (p.Arg381Cys) has been reported to be associated with RRM1-related disorder (ClinVar ID: VCV002664486 / PMID: 35617047). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.025
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;.
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.029
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Benign
0.26
Sift
Uncertain
0.0030
D;D
Sift4G
Benign
0.19
T;T
Polyphen
0.98
D;.
Vest4
0.58
MutPred
0.62
Loss of MoRF binding (P = 0.035);.;
MVP
0.44
MPC
0.82
ClinPred
0.97
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.75
gMVP
0.62

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2094584404; hg19: chr11-4144436; API