rs1553385828

Positions:

• chr2-69327044-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001244710.2(GFPT1):​c.1925A>T​(p.Asp642Val) 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 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: 7.89

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.1925A>T	p.Asp642Val	missense_variant	19/20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.1871A>T	p.Asp624Val	missense_variant	18/19		NP_002047.2
GFPT1	XM_017003801.2	c.2000A>T	p.Asp667Val	missense_variant	19/20		XP_016859290.1
GFPT1	XM_017003802.3	c.1946A>T	p.Asp649Val	missense_variant	18/19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.1925A>T	p.Asp642Val	missense_variant	19/20	5	NM_001244710.2	ENSP00000349860.4
GFPT1	ENST00000361060.5	c.1871A>T	p.Asp624Val	missense_variant	18/19	1		ENSP00000354347.4
GFPT1	ENST00000674507.1	c.1703A>T	p.Asp568Val	missense_variant	17/18			ENSP00000501332.1
GFPT1	ENST00000674438.1	c.1655A>T	p.Asp552Val	missense_variant	16/17			ENSP00000501469.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 06, 2017

This sequence change replaces aspartic acid with valine at codon 624 of the GFPT1 protein (p.Asp624Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GFPT1-related disease. 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 C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.40
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.88	.;P
Vest4		0.74
MutPred		0.64		Loss of disorder (P = 0.0301);.;
MVP		0.51
MPC		2.4
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.97

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: rs1553385828; hg19: chr2-69554176;