Genetic Variant NM_000884.3:c.787C>G (chr3-49026719-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000884.3(IMPDH2):c.787C>G(p.Leu263Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L263F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

IMPDH2
NM_000884.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.50

Publications

0 publications found

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]

IMPDH2 links:

ENSG00000290315 (HGNC:):

ENSG00000290315 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.503 (below the threshold of 3.09). Trascript score misZ: 3.3023 (above the threshold of 3.09).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000884.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IMPDH2	NM_000884.3	MANE Select	c.787C>G	p.Leu263Val	missense	Exon 7 of 14	NP_000875.2	P12268
IMPDH2	NM_001410759.1		c.787C>G	p.Leu263Val	missense	Exon 7 of 15	NP_001397688.1	H0Y4R1
IMPDH2	NM_001410760.1		c.712C>G	p.Leu238Val	missense	Exon 6 of 14	NP_001397689.1	A0A7I2YQK5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IMPDH2	ENST00000326739.9	TSL:1 MANE Select	c.787C>G	p.Leu263Val	missense	Exon 7 of 14	ENSP00000321584.4	P12268
ENSG00000290315	ENST00000703936.1		c.2827C>G	p.Leu943Val	missense	Exon 15 of 22	ENSP00000515567.1	A0A994J749
IMPDH2	ENST00000937815.1		c.955C>G	p.Leu319Val	missense	Exon 7 of 14	ENSP00000607874.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

4.1

PhyloP100

3.5

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.69

Sift

Uncertain

0.013

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.89

MutPred

0.80

Gain of glycosylation at Y258 (P = 0.0838)

MVP

0.94

MPC

0.96

ClinPred

0.99

GERP RS

5.6

Varity_R

0.88

gMVP

0.87

Mutation Taster

=23/77

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over