2-69338460-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F437L) has been classified 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 5 ACMG points.

• PM1: In a domain SIS 1 (size 139) in uniprot entity GFPT1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001244710.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GFPT1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFPT1	NM_001244710.2	c.1309T>A	p.Phe437Ile	missense_variant	14/20	ENST00000357308.9
GFPT1	NM_002056.4	c.1255T>A	p.Phe419Ile	missense_variant	13/19
GFPT1	XM_017003801.2	c.1384T>A	p.Phe462Ile	missense_variant	14/20
GFPT1	XM_017003802.3	c.1330T>A	p.Phe444Ile	missense_variant	13/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFPT1	ENST00000357308.9	c.1309T>A	p.Phe437Ile	missense_variant	14/20	5	NM_001244710.2
GFPT1	ENST00000361060.5	c.1255T>A	p.Phe419Ile	missense_variant	13/19	1		P1
GFPT1	ENST00000674507.1	c.1255T>A	p.Phe419Ile	missense_variant	13/18
GFPT1	ENST00000674438.1	c.1039T>A	p.Phe347Ile	missense_variant	11/17

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 08, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with GFPT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with isoleucine at codon 419 of the GFPT1 protein (p.Phe419Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. -

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;.
MutationTaster	Benign	1.0	D;D
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;