14-24235998-C-T

Variant names:

• chr14-24235998-C-T
• rs1223799692
• NM_001002002.3:c.323C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001002002.3(GMPR2):​c.323C>T​(p.Ser108Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 0.756
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23316029).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPR2	NM_001002002.3	c.323C>T	p.Ser108Phe	missense_variant	Exon 5 of 10	ENST00000399440.7	NP_001002002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPR2	ENST00000399440.7	c.323C>T	p.Ser108Phe	missense_variant	Exon 5 of 10	1	NM_001002002.3	ENSP00000382369.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377C>T (p.S126F) alteration is located in exon 4 (coding exon 4) of the GMPR2 gene. This alteration results from a C to T substitution at nucleotide position 377, causing the serine (S) at amino acid position 126 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	0.15
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D;T;T;D;D;T;D;.;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;M;.;.;.;.
PhyloP100		0.76
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;N;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.051	T;T;D;D;T;D;D;T;D;T;D;T
Sift4G	Benign	0.069	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;.;.;B;B;.;.;.
Vest4		0.20
MutPred		0.43		Gain of catalytic residue at S108 (P = 0.0102);Gain of catalytic residue at S108 (P = 0.0102);Gain of catalytic residue at S108 (P = 0.0102);Gain of catalytic residue at S108 (P = 0.0102);.;.;.;Gain of catalytic residue at S108 (P = 0.0102);.;.;.;.;
MVP		0.89
MPC		0.19
ClinPred		0.80	D
GERP RS		4.7
PromoterAI		-0.010	Neutral
Varity_R		0.52
gMVP		0.72
Mutation Taster		=76/24	polymorphism

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

dbSNP: rs1223799692; hg19: chr14-24705204;