rs72624905

Variant names:

• chr3-49028810-C-T
• rs72624905
• NM_000884.3:c.99-4G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000884.3(IMPDH2):​c.99-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000552 in 1,612,770 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: IMPDH2 NM_000884.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005592
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.44
• Publications: 2 publications found

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]

ENSG00000290315 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-49028810-C-T is Benign according to our data. Variant chr3-49028810-C-T is described in ClinVar as Benign. ClinVar VariationId is 775868.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 427 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH2	NM_000884.3	c.99-4G>A		splice_region_variant, intron_variant	Intron 1 of 13	ENST00000326739.9	NP_000875.2
IMPDH2	NM_001410759.1	c.99-4G>A		splice_region_variant, intron_variant	Intron 1 of 14		NP_001397688.1
IMPDH2	NM_001410760.1	c.99-4G>A		splice_region_variant, intron_variant	Intron 1 of 13		NP_001397689.1
IMPDH2	NM_001410761.1	c.99-4G>A		splice_region_variant, intron_variant	Intron 1 of 12		NP_001397690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH2	ENST00000326739.9	c.99-4G>A		splice_region_variant, intron_variant	Intron 1 of 13	1	NM_000884.3	ENSP00000321584.4
ENSG00000290315	ENST00000703936.1	c.2139-4G>A		splice_region_variant, intron_variant	Intron 9 of 21			ENSP00000515567.1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152034 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000801 AC: 201 AN: 251060 AF XY: 0.000663

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000317 AC: 463 AN: 1460620 Hom.: 3 Cov.: 30 AF XY: 0.000297 AC XY: 216 AN XY: 726690

African (AFR) AF: 0.0109 AC: 365 AN: 33448

American (AMR) AF: 0.000671 AC: 30 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1110882

Other (OTH) AF: 0.000613 AC: 37 AN: 60368

GnomAD4 genome AF: 0.00281 AC: 427 AN: 152150 Hom.: 4 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74392

African (AFR) AF: 0.00979 AC: 406 AN: 41458

American (AMR) AF: 0.000850 AC: 13 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00336

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

IMPDH2-related disorder Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Aug 14, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.50
DANN	Benign	0.83
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72624905; hg19: chr3-49066243;