3-49025254-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000884.3(IMPDH2):​c.1022G>A​(p.Arg341Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

IMPDH2
NM_000884.3 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.25
Variant links:
Genes affected
IMPDH2 (HGNC:6053): (inosine monophosphate dehydrogenase 2) This gene encodes the rate-limiting enzyme in the de novo guanine nucleotide biosynthesis. It is thus involved in maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. The encoded protein catalyzes the NAD-dependent oxidation of inosine-5'-monophosphate into xanthine-5'-monophosphate, which is then converted into guanosine-5'-monophosphate. This gene is up-regulated in some neoplasms, suggesting it may play a role in malignant transformation. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IMPDH2NM_000884.3 linkc.1022G>A p.Arg341Gln missense_variant Exon 10 of 14 ENST00000326739.9 NP_000875.2 P12268A0A384N6C2
IMPDH2NM_001410759.1 linkc.1094G>A p.Arg365Gln missense_variant Exon 11 of 15 NP_001397688.1
IMPDH2NM_001410760.1 linkc.1019G>A p.Arg340Gln missense_variant Exon 10 of 14 NP_001397689.1
IMPDH2NM_001410761.1 linkc.947G>A p.Arg316Gln missense_variant Exon 9 of 13 NP_001397690.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IMPDH2ENST00000326739.9 linkc.1022G>A p.Arg341Gln missense_variant Exon 10 of 14 1 NM_000884.3 ENSP00000321584.4 P12268
ENSG00000290315ENST00000703936.1 linkc.3062G>A p.Arg1021Gln missense_variant Exon 18 of 22 ENSP00000515567.1 A0A994J749

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jul 12, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.92
D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.5
D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.011
D
Sift4G
Benign
0.14
T
Polyphen
0.94
P
Vest4
0.67
MutPred
0.63
Loss of methylation at R341 (P = 0.0185);
MVP
0.94
MPC
2.5
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.97
gMVP
0.94

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.

Other links and lift over

dbSNP: rs2093193140; hg19: chr3-49062687; API