dbSNP rs2228121: RRM1:p.Leu121Met (chr11-4107509-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001033.5(RRM1):c.361T>A(p.Leu121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L121L) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RRM1
NM_001033.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.16

Publications

0 publications found

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]

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

RRM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13049954).

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.361T>A	p.Leu121Met	missense	Exon 4 of 19	NP_001024.1	P23921
	RRM1	NM_001318064.1		c.70T>A	p.Leu24Met	missense	Exon 3 of 18	NP_001304993.1	B4E0I8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRM1	ENST00000300738.10	TSL:1 MANE Select	c.361T>A	p.Leu121Met	missense	Exon 4 of 19	ENSP00000300738.5	P23921
RRM1	ENST00000854928.1		c.361T>A	p.Leu121Met	missense	Exon 4 of 19	ENSP00000524987.1
RRM1	ENST00000854929.1		c.361T>A	p.Leu121Met	missense	Exon 4 of 18	ENSP00000524988.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460744

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111056

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.014

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.32

PhyloP100

1.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.050

REVEL

Benign

0.13

Sift

Benign

0.13

Sift4G

Benign

0.084

Polyphen

0.039

Vest4

0.47

MutPred

0.36

Gain of catalytic residue at L121 (P = 0.0374)

MVP

0.31

MPC

0.84

ClinPred

0.31

GERP RS

-0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.81

Mutation Taster

=69/31

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over