14-24233594-G-T

Variant names:

• chr14-24233594-G-T
• NM_001002002.3:c.203G>T

Variant summary

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

The NM_001002002.3(GMPR2):​c.203G>T​(p.Cys68Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GMPR2 NM_001002002.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• Publications: 0 publications found

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]

ACMG classification

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	c.203G>T	p.Cys68Phe	missense_variant	Exon 3 of 10	ENST00000399440.7	NP_001002002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPR2	ENST00000399440.7	c.203G>T	p.Cys68Phe	missense_variant	Exon 3 of 10	1	NM_001002002.3	ENSP00000382369.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.257G>T (p.C86F) alteration is located in exon 2 (coding exon 2) of the GMPR2 gene. This alteration results from a G to T substitution at nucleotide position 257, causing the cysteine (C) at amino acid position 86 to be replaced by a phenylalanine (F). 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	0.21
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.60	.;D;D;D;D;.;T;T;D;.;.;.;.
Eigen	Benign	0.036
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.5	.;L;L;.;.;.;.;.;L;.;.;.;L
PhyloP100		2.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	.;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;T;D;D;D;D;D;D;D
Polyphen		0.48, 0.58	.;P;P;.;.;.;.;.;P;P;.;.;.
Vest4		0.46
MutPred		0.66		Loss of methylation at K69 (P = 0.0286);Loss of methylation at K69 (P = 0.0286);Loss of methylation at K69 (P = 0.0286);Loss of methylation at K69 (P = 0.0286);Loss of methylation at K69 (P = 0.0286);Loss of methylation at K69 (P = 0.0286);Loss of methylation at K69 (P = 0.0286);.;Loss of methylation at K69 (P = 0.0286);.;.;.;Loss of methylation at K69 (P = 0.0286);
MVP		0.91
MPC		0.29
ClinPred		0.89	D
GERP RS		4.1
Varity_R		0.90
gMVP		0.84
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr14-24702800;