3-49026756-A-C

Variant names:

• chr3-49026756-A-C
• rs760008447
• NM_000884.3:c.750T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000884.3(IMPDH2):​c.750T>G​(p.Ile250Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I250S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: IMPDH2 NM_000884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.598
• 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: Likely_benign. The variant received -3 ACMG points.

• 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).
• BS2: High AC in GnomAdExome4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPDH2	NM_000884.3	MANE Select	c.750T>G	p.Ile250Met	missense	Exon 7 of 14	NP_000875.2	P12268
	IMPDH2	NM_001410759.1		c.750T>G	p.Ile250Met	missense	Exon 7 of 15	NP_001397688.1	H0Y4R1
	IMPDH2	NM_001410760.1		c.675T>G	p.Ile225Met	missense	Exon 6 of 14	NP_001397689.1	A0A7I2YQK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPDH2	ENST00000326739.9	TSL:1 MANE Select	c.750T>G	p.Ile250Met	missense	Exon 7 of 14	ENSP00000321584.4	P12268
	ENSG00000290315	ENST00000703936.1		c.2790T>G	p.Ile930Met	missense	Exon 15 of 22	ENSP00000515567.1	A0A994J749
	IMPDH2	ENST00000937815.1		c.918T>G	p.Ile306Met	missense	Exon 7 of 14	ENSP00000607874.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251496 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		-0.60
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.57	P
Vest4		0.91
MutPred		0.81		Gain of disorder (P = 0.0562)
MVP		0.77
MPC		1.1
ClinPred		0.55	D
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.92
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs760008447; hg19: chr3-49064189;