11-4135094-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001033.5(RRM1):​c.2014A>G​(p.Ile672Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,457,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

RRM1
NM_001033.5 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.31081963).
BS2
High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RRM1NM_001033.5 linkc.2014A>G p.Ile672Val missense_variant Exon 18 of 19 ENST00000300738.10 NP_001024.1 P23921
RRM1NM_001318064.1 linkc.1723A>G p.Ile575Val missense_variant Exon 17 of 18 NP_001304993.1 P23921B4E0I8
RRM1NM_001330193.1 linkc.1348A>G p.Ile450Val missense_variant Exon 12 of 13 NP_001317122.1 E9PL69
RRM1NM_001318065.1 linkc.1000A>G p.Ile334Val missense_variant Exon 12 of 13 NP_001304994.1 P23921B4DXD1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RRM1ENST00000300738.10 linkc.2014A>G p.Ile672Val missense_variant Exon 18 of 19 1 NM_001033.5 ENSP00000300738.5 P23921

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249028
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134574
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000148
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:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000329
AC:
48
AN:
1457162
Hom.:
0
Cov.:
30
AF XY:
0.0000331
AC XY:
24
AN XY:
724368
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000158
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:
0.0000334
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000302
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000595

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 26, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2014A>G (p.I672V) alteration is located in exon 18 (coding exon 18) of the RRM1 gene. This alteration results from a A to G substitution at nucleotide position 2014, causing the isoleucine (I) at amino acid position 672 to be replaced by a valine (V). 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
0.15
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.31
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.98
N;N
REVEL
Benign
0.23
Sift
Benign
0.090
T;T
Sift4G
Benign
0.096
T;T
Polyphen
0.39
B;.
Vest4
0.34
MutPred
0.65
Gain of helix (P = 0.132);.;
MVP
0.45
MPC
0.57
ClinPred
0.24
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.78

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779191139; hg19: chr11-4156324; API