6-16254601-G-A

Position:

• chr6-16254601-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006877.4(GMPR):​c.331G>A​(p.Glu111Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,784 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: 0.0000014 (0 hom.)
• Consequence: GMPR NM_006877.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

Genes affected

GMPR (HGNC:4376): (guanosine monophosphate reductase) This gene encodes an enzyme that catalyzes the irreversible and NADPH-dependent reductive deamination of GMP to IMP. The protein also functions in the re-utilization of free intracellular bases and purine nucleosides.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMPR	NM_006877.4	c.331G>A	p.Glu111Lys	missense_variant	4/9	ENST00000259727.5
GMPR	XM_047418656.1	c.331G>A	p.Glu111Lys	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMPR	ENST00000259727.5	c.331G>A	p.Glu111Lys	missense_variant	4/9	1	NM_006877.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461784 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.331G>A (p.E111K) alteration is located in exon 4 (coding exon 4) of the GMPR gene. This alteration results from a G to A substitution at nucleotide position 331, causing the glutamic acid (E) at amino acid position 111 to be replaced by a lysine (K). 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	0.095
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.35
Sift	Benign	0.12	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.43
MutPred		0.59		Gain of methylation at E111 (P = 0.0245);
MVP		0.91
MPC		0.090
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs1240671486; hg19: chr6-16254832; COSMIC: COSV52471896; COSMIC: COSV52471896;