Genetic Variant GMPR2:p.Ile180Asn (chr14-24237144-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001002002.3(GMPR2):c.539T>A(p.Ile180Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,556 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: 0.0000014 ( 0 hom. )

Consequence

GMPR2
NM_001002002.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.01

Publications

0 publications found

Variant links:

Genes affected

GMPR2 (HGNC:4377): (guanosine monophosphate reductase 2) This gene encodes an enzyme that catalyzes the irreversible and NADPH-dependent reductive deamination of guanosine monophosphate (GMP) to inosine monophosphate (IMP). The protein also functions in the re-utilization of free intracellular bases and purine nucleosides. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

GMPR2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPR2	NM_001002002.3 link	c.539T>A	p.Ile180Asn	missense_variant	Exon 6 of 10	ENST00000399440.7	NP_001002002.1	Q9P2T1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPR2	ENST00000399440.7 link	c.539T>A	p.Ile180Asn	missense_variant	Exon 6 of 10	1	NM_001002002.3	ENSP00000382369.2		Q9P2T1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724536

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106220

Other (OTH)

AF:

0.00

AC:

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.593T>A (p.I198N) alteration is located in exon 5 (coding exon 5) of the GMPR2 gene. This alteration results from a T to A substitution at nucleotide position 593, causing the isoleucine (I) at amino acid position 198 to be replaced by an asparagine (N). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

.;D;D;D;.;D;D;D;.;.;.;.;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.080

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

5.0

.;H;H;.;.;.;.;H;.;.;.;.;.

PhyloP100

8.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.7

.;D;D;D;.;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

.;D;D;D;.;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;.;.;.;.;D;D;.;.;.;.

Vest4

0.90

MutPred

0.86

Loss of catalytic residue at P182 (P = 0.0521);Loss of catalytic residue at P182 (P = 0.0521);Loss of catalytic residue at P182 (P = 0.0521);.;.;.;.;Loss of catalytic residue at P182 (P = 0.0521);.;.;.;.;.;

MVP

1.0

MPC

0.94

ClinPred

1.0

GERP RS

5.4

PromoterAI

-0.0086

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.92

Mutation Taster

=4/96

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over