Variant 2-10123390-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001034.4(RRM2):c.178A>G(p.Thr60Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RRM2
NM_001034.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0150

Variant links:

Genes affected

RRM2 (HGNC:10452): (ribonucleotide reductase regulatory subunit M2) This gene encodes one of two non-identical subunits for ribonucleotide reductase. This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion. Transcription from this gene can initiate from alternative promoters, which results in two isoforms that differ in the lengths of their N-termini. Related pseudogenes have been identified on chromosomes 1 and X. [provided by RefSeq, Sep 2009]

RRM2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061879456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RRM2	NM_001034.4 linkuse as main transcript	c.178A>G	p.Thr60Ala	missense_variant	3/10	ENST00000304567.10
RRM2	NM_001165931.1 linkuse as main transcript	c.358A>G	p.Thr120Ala	missense_variant	3/10
RRM2	NR_164157.1 linkuse as main transcript	n.238A>G		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM2	ENST00000304567.10 linkuse as main transcript	c.178A>G	p.Thr60Ala	missense_variant	3/10	1	NM_001034.4	P1	P31350-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449658

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721990

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.358A>G (p.T120A) alteration is located in exon 3 (coding exon 3) of the RRM2 gene. This alteration results from a A to G substitution at nucleotide position 358, causing the threonine (T) at amino acid position 120 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

0.0057

BayesDel_noAF

Benign

-0.23

CADD

Benign

0.54

DANN

Benign

0.86

DEOGEN2

Benign

0.11

T;.;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.27

.;.;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.062

T;T;T;T;T

MetaSVM

Uncertain

-0.055

MutationAssessor

Benign

0.34

N;.;.;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.31

.;N;.;N;N

REVEL

Benign

0.26

Sift

Benign

0.31

.;T;.;T;T

Sift4G

Benign

0.75

.;T;T;T;T

Polyphen

0.0

B;.;.;B;.

Vest4

0.064, 0.070, 0.062

MutPred

0.16

Loss of phosphorylation at T60 (P = 0.0017);.;.;Loss of phosphorylation at T60 (P = 0.0017);.;

MVP

0.43

MPC

0.67

ClinPred

0.049

GERP RS

-5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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