2-69338460-A-T

Variant names:

• chr2-69338460-A-T
• rs766450555
• NM_001244710.2:c.1309T>A

Variant summary

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

The NM_001244710.2(GFPT1):​c.1309T>A​(p.Phe437Ile) variant causes a missense change involving the alteration of a 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: GFPT1 NM_001244710.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

Genes affected

GFPT1 (HGNC:4241): (glutamine--fructose-6-phosphate transaminase 1) This gene encodes the first and rate-limiting enzyme of the hexosamine pathway and controls the flux of glucose into the hexosamine pathway. The product of this gene catalyzes the formation of glucosamine 6-phosphate. [provided by RefSeq, Sep 2008]

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 rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.1309T>A	p.Phe437Ile	missense_variant	Exon 14 of 20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.1255T>A	p.Phe419Ile	missense_variant	Exon 13 of 19		NP_002047.2
GFPT1	XM_017003801.2	c.1384T>A	p.Phe462Ile	missense_variant	Exon 14 of 20		XP_016859290.1
GFPT1	XM_017003802.3	c.1330T>A	p.Phe444Ile	missense_variant	Exon 13 of 19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.1309T>A	p.Phe437Ile	missense_variant	Exon 14 of 20	5	NM_001244710.2	ENSP00000349860.4
GFPT1	ENST00000361060.5	c.1255T>A	p.Phe419Ile	missense_variant	Exon 13 of 19	1		ENSP00000354347.4
GFPT1	ENST00000674507.1	c.1255T>A	p.Phe419Ile	missense_variant	Exon 13 of 18			ENSP00000501332.1
GFPT1	ENST00000674438.1	c.1039T>A	p.Phe347Ile	missense_variant	Exon 11 of 17			ENSP00000501469.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 12 Uncertain:1

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 437 of the GFPT1 protein (p.Phe437Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GFPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 473127). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFPT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.098	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		1.0	.;D
Vest4		0.61
MutPred		0.52		Loss of catalytic residue at F437 (P = 0.0057);.;
MVP		0.85
MPC		2.7
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99

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: rs766450555; hg19: chr2-69565592;