11-4123206-G-A
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
RRM1
NM_001033.5 missense
NM_001033.5 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 6.89
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RRM1 | NM_001033.5 | c.1142G>A | p.Arg381His | missense_variant | 12/19 | ENST00000300738.10 | NP_001024.1 | |
RRM1 | NM_001318064.1 | c.851G>A | p.Arg284His | missense_variant | 11/18 | NP_001304993.1 | ||
RRM1 | NM_001330193.1 | c.476G>A | p.Arg159His | missense_variant | 6/13 | NP_001317122.1 | ||
RRM1 | NM_001318065.1 | c.128G>A | p.Arg43His | missense_variant | 6/13 | NP_001304994.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RRM1 | ENST00000300738.10 | c.1142G>A | p.Arg381His | missense_variant | 12/19 | 1 | NM_001033.5 | ENSP00000300738.5 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151994Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
151994
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461774Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727206
GnomAD4 exome
AF:
AC:
2
AN:
1461774
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727206
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151994Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74236
GnomAD4 genome
AF:
AC:
1
AN:
151994
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74236
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 07, 2023 | - - |
RRM1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | 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). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.035);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at