3-49026709-G-C

Variant names:

• chr3-49026709-G-C
• NM_000884.3:c.797C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000884.3(IMPDH2):​c.797C>G​(p.Ala266Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IMPDH2 NM_000884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH2	NM_000884.3	c.797C>G	p.Ala266Gly	missense_variant	Exon 7 of 14	ENST00000326739.9	NP_000875.2
IMPDH2	NM_001410759.1	c.797C>G	p.Ala266Gly	missense_variant	Exon 7 of 15		NP_001397688.1
IMPDH2	NM_001410760.1	c.722C>G	p.Ala241Gly	missense_variant	Exon 6 of 14		NP_001397689.1
IMPDH2	NM_001410761.1	c.722C>G	p.Ala241Gly	missense_variant	Exon 6 of 13		NP_001397690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH2	ENST00000326739.9	c.797C>G	p.Ala266Gly	missense_variant	Exon 7 of 14	1	NM_000884.3	ENSP00000321584.4
ENSG00000290315	ENST00000703936.1	c.2837C>G	p.Ala946Gly	missense_variant	Exon 15 of 22			ENSP00000515567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.797C>G (p.A266G) alteration is located in exon 7 (coding exon 7) of the IMPDH2 gene. This alteration results from a C to G substitution at nucleotide position 797, causing the alanine (A) at amino acid position 266 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.66	P;.
Vest4		0.49
MutPred		0.80		Loss of catalytic residue at A266 (P = 0.0171);.;
MVP		0.92
MPC		0.95
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49064142;