NM_001244710.2:c.147T>A

Variant names:

• chr2-69370077-A-T
• rs2230300
• NM_001244710.2:c.147T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001244710.2(GFPT1):​c.147T>A​(p.Asp49Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D49Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFPT1 NM_001244710.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.441
• 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 1 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=0.089969546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.147T>A	p.Asp49Glu	missense_variant	Exon 3 of 20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.147T>A	p.Asp49Glu	missense_variant	Exon 3 of 19		NP_002047.2
GFPT1	XM_017003801.2	c.222T>A	p.Asp74Glu	missense_variant	Exon 3 of 20		XP_016859290.1
GFPT1	XM_017003802.3	c.222T>A	p.Asp74Glu	missense_variant	Exon 3 of 19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.147T>A	p.Asp49Glu	missense_variant	Exon 3 of 20	5	NM_001244710.2	ENSP00000349860.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.090	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N;N
PhyloP100		-0.44
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.12
Sift	Benign	0.39	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0010	.;B
Vest4		0.20
MutPred		0.41		Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.25
MPC		0.54
ClinPred		0.096	T
GERP RS		-2.9
Varity_R		0.034
gMVP		0.57
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230300; hg19: chr2-69597209;