1-74199699-G-C

Variant names:

• chr1-74199699-G-C
• rs1428899793
• NM_003838.5:c.118G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003838.5(FPGT):​c.118G>C​(p.Val40Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V40I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FPGT NM_003838.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.38
• Publications: 0 publications found

Genes affected

FPGT (HGNC:3825): (fucose-1-phosphate guanylyltransferase) L-fucose is a key sugar in glycoproteins and other complex carbohydrates since it may be involved in many of the functional roles of these macromolecules, such as in cell-cell recognition. The fucosyl donor for these fucosylated oligosaccharides is GDP-beta-L-fucose. There are two alternate pathways for the biosynthesis of GDP-fucose; the major pathway converts GDP-alpha-D-mannose to GDP-beta-L-fucose. The protein encoded by this gene participates in an alternate pathway that is present in certain mammalian tissues, such as liver and kidney, and appears to function as a salvage pathway to reutilize L-fucose arising from the turnover of glycoproteins and glycolipids. This pathway involves the phosphorylation of L-fucose to form beta-L-fucose-1-phosphate, and then condensation of the beta-L-fucose-1-phosphate with GTP by fucose-1-phosphate guanylyltransferase to form GDP-beta-L-fucose. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream TNNI3 interacting kinase (TNNI3K) gene. [provided by RefSeq, Dec 2010]

FPGT-TNNI3K (HGNC:42952): (FPGT-TNNI3K readthrough) Enables protein C-terminus binding activity; protein kinase activity; and troponin I binding activity. Involved in protein phosphorylation and regulation of heart contraction. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGT	NM_003838.5	c.118G>C	p.Val40Leu	missense_variant	Exon 2 of 4	ENST00000370898.9	NP_003829.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGT	ENST00000370898.9	c.118G>C	p.Val40Leu	missense_variant	Exon 2 of 4	1	NM_003838.5	ENSP00000359935.4
FPGT-TNNI3K	ENST00000557284.7	c.118G>C	p.Val40Leu	missense_variant	Exon 2 of 27	2		ENSP00000450895.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.0	.;.;M;.;M;.;.;.;.;.;.
PhyloP100		5.4
PROVEAN	Uncertain	-2.5	.;.;D;D;N;N;.;N;N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.012	.;.;D;D;D;T;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.55
MutPred		0.58		.;.;Loss of catalytic residue at V40 (P = 0.0413);.;Loss of catalytic residue at V40 (P = 0.0413);.;.;Loss of catalytic residue at V40 (P = 0.0413);Loss of catalytic residue at V40 (P = 0.0413);Loss of catalytic residue at V40 (P = 0.0413);Loss of catalytic residue at V40 (P = 0.0413);
MVP		0.50
MPC		0.023
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.053
gMVP		0.37
Mutation Taster		=78/22	polymorphism

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: rs1428899793; hg19: chr1-74665383;