rs766450555

Positions:

• chr2-69338460-A-G
• chr2-69338460-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001244710.2(GFPT1):​c.1309T>C​(p.Phe437Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFPT1 NM_001244710.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain SIS 1 (size 139) in uniprot entity GFPT1_HUMAN there are 8 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 in gene, where missense usually causes diseases (based on misZ statistic), GFPT1. . Gene score misZ 4.3482 (greater than the threshold 3.09). Trascript score misZ 4.3487 (greater than threshold 3.09). GenCC has associacion of gene with congenital myasthenic syndromes with glycosylation defect, congenital myasthenic syndrome 12.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 2-69338460-A-G is Pathogenic according to our data. Variant chr2-69338460-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 986215.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.1309T>C	p.Phe437Leu	missense_variant	14/20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.1255T>C	p.Phe419Leu	missense_variant	13/19		NP_002047.2
GFPT1	XM_017003801.2	c.1384T>C	p.Phe462Leu	missense_variant	14/20		XP_016859290.1
GFPT1	XM_017003802.3	c.1330T>C	p.Phe444Leu	missense_variant	13/19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.1309T>C	p.Phe437Leu	missense_variant	14/20	5	NM_001244710.2	ENSP00000349860.4
GFPT1	ENST00000361060.5	c.1255T>C	p.Phe419Leu	missense_variant	13/19	1		ENSP00000354347.4
GFPT1	ENST00000674507.1	c.1255T>C	p.Phe419Leu	missense_variant	13/18			ENSP00000501332.1
GFPT1	ENST00000674438.1	c.1039T>C	p.Phe347Leu	missense_variant	11/17			ENSP00000501469.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

GFPT1-related myopathy with protein aggregates and rimmed vacuoles Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PVS1+PS3+PM2+PP3+PP4+PP5 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1255T>C (p.F419L) alteration is located in coding exon 13 of the GFPT1 gene. This alteration results from a T to C substitution at nucleotide position 1255, causing the phenylalanine (F) at amino acid position 419 to be replaced by a leucine (L). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GFPT1 c.1255T>C alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.F419 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.F419L alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2023

This variant has not been reported in the literature in individuals affected with GFPT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 437 of the GFPT1 protein (p.Phe437Leu). ClinVar contains an entry for this variant (Variation ID: 986215). 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt GFPT1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	.;D
Vest4		0.69
MutPred		0.52		Loss of catalytic residue at F437 (P = 0.083);.;
MVP		0.76
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98

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;