11-4127054-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_001033.5(RRM1):c.1490G>A(p.Arg497His) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,610,124 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R497C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

RRM1
NM_001033.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant where missense usually causes diseases, RRM1

BP4

Computational evidence support a benign effect (MetaRNN=0.011275202).

BP6

Variant 11-4127054-G-A is Benign according to our data. Variant chr11-4127054-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 776564.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RRM1	NM_001033.5 linkuse as main transcript	c.1490G>A	p.Arg497His	missense_variant	14/19	ENST00000300738.10
RRM1	NM_001318064.1 linkuse as main transcript	c.1199G>A	p.Arg400His	missense_variant	13/18
RRM1	NM_001330193.1 linkuse as main transcript	c.824G>A	p.Arg275His	missense_variant	8/13
RRM1	NM_001318065.1 linkuse as main transcript	c.476G>A	p.Arg159His	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM1	ENST00000300738.10 linkuse as main transcript	c.1490G>A	p.Arg497His	missense_variant	14/19	1	NM_001033.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

310

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00686

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000545

AC:

135

AN:

247628

Hom.:

AF XY:

0.000374

AC XY:

AN XY:

133820

show subpopulations

Gnomad AFR exome

AF:

0.00747

Gnomad AMR exome

AF:

0.000359

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000192

AC:

280

AN:

1457912

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

725186

show subpopulations

Gnomad4 AFR exome

AF:

0.00663

Gnomad4 AMR exome

AF:

0.000506

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.000448

GnomAD4 genome

AF:

0.00204

AC:

310

AN:

152212

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00684

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000284

Hom.:

Bravo

AF:

0.00244

ESP6500AA

AF:

0.00818

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000717

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.88

P;.

Vest4

0.25

MVP

0.73

MPC

0.93

ClinPred

0.17

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.83

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over