Genetic Variant GMPR2:p.Val139Ile (chr14-24236090-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001002002.3(GMPR2):c.415G>A(p.Val139Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GMPR2
NM_001002002.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPR2	NM_001002002.3 link	c.415G>A	p.Val139Ile	missense_variant	Exon 5 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.415G>A	p.Val139Ile	missense_variant	Exon 5 of 10	1	NM_001002002.3	ENSP00000382369.2		Q9P2T1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111914

Other (OTH)

AF:

0.00

AC:

AN:

60388

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

Aug 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.469G>A (p.V157I) alteration is located in exon 4 (coding exon 4) of the GMPR2 gene. This alteration results from a G to A substitution at nucleotide position 469, causing the valine (V) at amino acid position 157 to be replaced by an isoleucine (I). 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

0.15

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;T;T;.;T;T;T;.;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.43

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.037

MutationAssessor

Benign

0.96

.;L;L;.;.;.;L;.;.;.

PhyloP100

9.6

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.87

.;N;N;.;N;N;N;N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.085

.;T;T;.;T;T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T;T;T;T;T;T

Polyphen

0.46, 0.66

.;P;P;.;.;.;P;P;.;.

Vest4

0.43

MutPred

0.42

Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;.;Gain of helix (P = 0.132);.;.;.;

MVP

0.72

MPC

0.28

ClinPred

0.62

GERP RS

5.5

PromoterAI

-0.064

Neutral

(source)

Varity_R

0.56

gMVP

0.68

Mutation Taster

=44/56

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