Genetic Variant GFPT2:p.Ile563Val (chr5-180304927-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_005110.4(GFPT2):c.1687A>G(p.Ile563Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I563R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GFPT2
NM_005110.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

GFPT2 (HGNC:4242): (glutamine-fructose-6-phosphate transaminase 2) Predicted to enable glutamine-fructose-6-phosphate transaminase (isomerizing) activity. Predicted to be involved in UDP-N-acetylglucosamine metabolic process; fructose 6-phosphate metabolic process; and protein N-linked glycosylation. Predicted to act upstream of or within cellular response to leukemia inhibitory factor. Predicted to be located in cytosol. Implicated in type 2 diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

GFPT2 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
GFPT2	NM_005110.4 link	c.1687A>G	p.Ile563Val	missense_variant	Exon 17 of 19	ENST00000253778.13	NP_005101.1	O94808A0A0S2Z4X9B3KMR8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFPT2	ENST00000253778.13 link	c.1687A>G	p.Ile563Val	missense_variant	Exon 17 of 19	1	NM_005110.4	ENSP00000253778.8		O94808

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248934

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135050

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455812

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1687A>G (p.I563V) alteration is located in exon 17 (coding exon 17) of the GFPT2 gene. This alteration results from a A to G substitution at nucleotide position 1687, causing the isoleucine (I) at amino acid position 563 to be replaced by a valine (V). 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

Benign

-0.049

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.77

REVEL

Benign

0.23

Sift

Benign

0.39

Sift4G

Benign

0.28

Polyphen

0.011

Vest4

0.66

MutPred

0.76

Gain of helix (P = 0.0425);

MVP

0.64

MPC

0.35

ClinPred

0.32

GERP RS

5.8

Varity_R

0.15

gMVP

0.53

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over