rs1553386276

Variant names:

• chr2-69329747-C-T
• rs1553386276
• NM_001244710.2:c.1534G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001244710.2(GFPT1):​c.1534G>A​(p.Asp512Asn) 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 benign 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: 7.81
• Publications: 0 publications found

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]

GFPT1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 12

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Illumina
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.3482 (above the threshold of 3.09). Trascript score misZ: 4.3487 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 12, congenital myasthenic syndromes with glycosylation defect.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35787597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.1534G>A	p.Asp512Asn	missense_variant	Exon 16 of 20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.1480G>A	p.Asp494Asn	missense_variant	Exon 15 of 19		NP_002047.2
GFPT1	XM_017003801.2	c.1609G>A	p.Asp537Asn	missense_variant	Exon 16 of 20		XP_016859290.1
GFPT1	XM_017003802.3	c.1555G>A	p.Asp519Asn	missense_variant	Exon 15 of 19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.1534G>A	p.Asp512Asn	missense_variant	Exon 16 of 20	5	NM_001244710.2	ENSP00000349860.4
GFPT1	ENST00000361060.5	c.1480G>A	p.Asp494Asn	missense_variant	Exon 15 of 19	1		ENSP00000354347.4
GFPT1	ENST00000674507.1	c.1480G>A	p.Asp494Asn	missense_variant	Exon 15 of 18			ENSP00000501332.1
GFPT1	ENST00000674438.1	c.1264G>A	p.Asp422Asn	missense_variant	Exon 13 of 17			ENSP00000501469.1

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

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 473128). 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 494 of the GFPT1 protein (p.Asp494Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.16
Sift	Benign	0.065	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.43	.;B
Vest4		0.48
MutPred		0.32		Gain of MoRF binding (P = 0.0584);.;
MVP		0.75
MPC		1.3
ClinPred		0.93	D
GERP RS		5.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.39
gMVP		0.88
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs1553386276; hg19: chr2-69556879;