chr2-69342168-T-A

Position:

• chr2-69342168-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001244710.2(GFPT1):​c.1187A>T​(p.Tyr396Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.23

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
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.1187A>T	p.Tyr396Phe	missense_variant	13/20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.1133A>T	p.Tyr378Phe	missense_variant	12/19		NP_002047.2
GFPT1	XM_017003801.2	c.1262A>T	p.Tyr421Phe	missense_variant	13/20		XP_016859290.1
GFPT1	XM_017003802.3	c.1208A>T	p.Tyr403Phe	missense_variant	12/19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.1187A>T	p.Tyr396Phe	missense_variant	13/20	5	NM_001244710.2	ENSP00000349860
GFPT1	ENST00000361060.5	c.1133A>T	p.Tyr378Phe	missense_variant	12/19	1		ENSP00000354347	P1
GFPT1	ENST00000674507.1	c.1133A>T	p.Tyr378Phe	missense_variant	12/18			ENSP00000501332
GFPT1	ENST00000674438.1	c.917A>T	p.Tyr306Phe	missense_variant	10/17			ENSP00000501469

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Jun 27, 2022

This variant is not present in population databases (gnomAD no frequency). 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 C15"). ClinVar contains an entry for this variant (Variation ID: 473126). This variant has not been reported in the literature in individuals affected with GFPT1-related conditions. This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 378 of the GFPT1 protein (p.Tyr378Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Benign	0.067
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.25
Sift	Benign	0.18	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.031	.;B
Vest4		0.52
MutPred		0.73		Loss of phosphorylation at T394 (P = 0.2145);.;
MVP		0.59
MPC		1.4
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.52
gMVP		0.87

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: rs1553388418; hg19: chr2-69569300;