rs1553385828

Variant names:

• chr2-69327044-T-A
• rs1553385828
• NM_001244710.2:c.1925A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

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

Ensembl

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

Mar 06, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;