11-4123206-G-A

Variant names:

• chr11-4123206-G-A
• rs2094584404
• NM_001033.5:c.1142G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PM5 PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R381C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RRM1 NM_001033.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-4123205-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2664486.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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
RRM1	NM_001033.5	c.1142G>A	p.Arg381His	missense_variant	Exon 12 of 19	ENST00000300738.10	NP_001024.1
RRM1	NM_001318064.1	c.851G>A	p.Arg284His	missense_variant	Exon 11 of 18		NP_001304993.1
RRM1	NM_001330193.1	c.476G>A	p.Arg159His	missense_variant	Exon 6 of 13		NP_001317122.1
RRM1	NM_001318065.1	c.128G>A	p.Arg43His	missense_variant	Exon 6 of 13		NP_001304994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM1	ENST00000300738.10	c.1142G>A	p.Arg381His	missense_variant	Exon 12 of 19	1	NM_001033.5	ENSP00000300738.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 32

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

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33474

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86248

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 0.00000180 AC: 2 AN: 1111920

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000656 AC: 0.000065591 AN: 0.000065591

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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

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
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs2094584404; hg19: chr11-4144436;