Genetic Variant NM_000884.3:c.1504G>A (chr3-49024514-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000884.3(IMPDH2):c.1504G>A(p.Gly502Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IMPDH2
NM_000884.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.48

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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity IMDH2_HUMAN

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, 0.82

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.1504G>A	p.Gly502Ser	missense	Exon 13 of 14	NP_000875.2	P12268
IMPDH2	NM_001410759.1		c.1576G>A	p.Gly526Ser	missense	Exon 14 of 15	NP_001397688.1	H0Y4R1
IMPDH2	NM_001410760.1		c.1501G>A	p.Gly501Ser	missense	Exon 13 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.1504G>A	p.Gly502Ser	missense	Exon 13 of 14	ENSP00000321584.4	P12268
ENSG00000290315	ENST00000703936.1		c.3544G>A	p.Gly1182Ser	missense	Exon 21 of 22	ENSP00000515567.1	A0A994J749
IMPDH2	ENST00000937815.1		c.1672G>A	p.Gly558Ser	missense	Exon 13 of 14	ENSP00000607874.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.7

PhyloP100

7.5

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.65

Sift

Benign

0.097

Sift4G

Benign

0.097

Polyphen

0.64

Vest4

0.84

MutPred

0.54

Gain of glycosylation at S505 (P = 0.0297)

MVP

0.90

MPC

1.5

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.77

gMVP

0.89

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: 3

DS_DL_spliceai

0.26

Position offset: -19

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