Genetic Variant NM_000884.3:c.532-96G>A (chr3-49027143-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000884.3(IMPDH2):c.532-96G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 904,786 control chromosomes in the GnomAD database, including 938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.031 ( 105 hom., cov: 33)

Exomes 𝑓: 0.041 ( 833 hom. )

Consequence

IMPDH2
NM_000884.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.357

Publications

7 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0315 (4789/152198) while in subpopulation NFE AF = 0.0476 (3234/68012). AF 95% confidence interval is 0.0462. There are 105 homozygotes in GnomAd4. There are 2324 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4789 AD gene.

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	Effect	Exon Rank	Protein	UniProt
IMPDH2	NM_000884.3	MANE Select	c.532-96G>A	intron	N/A	NP_000875.2	P12268
IMPDH2	NM_001410759.1		c.532-96G>A	intron	N/A	NP_001397688.1	H0Y4R1
IMPDH2	NM_001410760.1		c.457-96G>A	intron	N/A	NP_001397689.1	A0A7I2YQK5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IMPDH2	ENST00000326739.9	TSL:1 MANE Select	c.532-96G>A	intron	N/A	ENSP00000321584.4	P12268
ENSG00000290315	ENST00000703936.1		c.2572-96G>A	intron	N/A	ENSP00000515567.1	A0A994J749
IMPDH2	ENST00000937815.1		c.700-96G>A	intron	N/A	ENSP00000607874.1

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

4790

AN:

152080

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00753

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0672

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0414

Gnomad FIN

AF:

0.0450

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0475

Gnomad OTH

AF:

0.0226

GnomAD4 exome

AF:

0.0411

AC:

30916

AN:

752588

Hom.:

833

AF XY:

0.0421

AC XY:

16870

AN XY:

400322

show subpopulations

African (AFR)

AF:

0.00670

AC:

132

AN:

19706

American (AMR)

AF:

0.0115

AC:

489

AN:

42368

Ashkenazi Jewish (ASJ)

AF:

0.0704

AC:

1517

AN:

21534

East Asian (EAS)

AF:

0.000934

AC:

AN:

36410

South Asian (SAS)

AF:

0.0473

AC:

3400

AN:

71880

European-Finnish (FIN)

AF:

0.0406

AC:

1774

AN:

43710

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

3574

European-Non Finnish (NFE)

AF:

0.0463

AC:

22051

AN:

476456

Other (OTH)

AF:

0.0395

AC:

1458

AN:

36950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1590

3180

4769

6359

7949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

404

808

1212

1616

2020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0315

AC:

4789

AN:

152198

Hom.:

105

Cov.:

AF XY:

0.0312

AC XY:

2324

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00751

AC:

312

AN:

41532

American (AMR)

AF:

0.0156

AC:

238

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0672

AC:

233

AN:

3468

East Asian (EAS)

AF:

0.00232

AC:

AN:

5176

South Asian (SAS)

AF:

0.0413

AC:

199

AN:

4824

European-Finnish (FIN)

AF:

0.0450

AC:

476

AN:

10586

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0476

AC:

3234

AN:

68012

Other (OTH)

AF:

0.0223

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

243

487

730

974

1217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0398

Hom.:

Bravo

AF:

0.0267

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.84

(source)

DANN

Benign

0.55

PhyloP100

-0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over