rs772026265

Positions:

• chr2-69327042-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001244710.2(GFPT1):​c.1927A>G​(p.Thr643Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GFPT1 NM_001244710.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.49

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 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.102721214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.1927A>G	p.Thr643Ala	missense_variant	19/20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.1873A>G	p.Thr625Ala	missense_variant	18/19		NP_002047.2
GFPT1	XM_017003801.2	c.2002A>G	p.Thr668Ala	missense_variant	19/20		XP_016859290.1
GFPT1	XM_017003802.3	c.1948A>G	p.Thr650Ala	missense_variant	18/19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.1927A>G	p.Thr643Ala	missense_variant	19/20	5	NM_001244710.2	ENSP00000349860.4
GFPT1	ENST00000361060.5	c.1873A>G	p.Thr625Ala	missense_variant	18/19	1		ENSP00000354347.4
GFPT1	ENST00000674507.1	c.1705A>G	p.Thr569Ala	missense_variant	17/18			ENSP00000501332.1
GFPT1	ENST00000674438.1	c.1657A>G	p.Thr553Ala	missense_variant	16/17			ENSP00000501469.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251442 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.1873A>G (p.T625A) alteration is located in exon 18 (coding exon 18) of the GFPT1 gene. This alteration results from a A to G substitution at nucleotide position 1873, causing the threonine (T) at amino acid position 625 to be replaced by an alanine (A). 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

May 03, 2018

This sequence change replaces threonine with alanine at codon 625 of the GFPT1 protein (p.Thr625Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs772026265, ExAC 0.002%). This variant has not been reported in the literature in individuals with GFPT1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Benign	0.064
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.40
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.38	N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	0.87	T;T
Polyphen		0.0	.;B
Vest4		0.21
MVP		0.32
MPC		1.1
ClinPred		0.21	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.35

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: rs772026265; hg19: chr2-69554174;