chr1-74199699-G-A

Position:

• chr1-74199699-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003838.5(FPGT):​c.118G>A​(p.Val40Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FPGT NM_003838.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2859112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FPGT	NM_003838.5	c.118G>A	p.Val40Ile	missense_variant	2/4	ENST00000370898.9
FPGT-TNNI3K	NM_001112808.3	c.118G>A	p.Val40Ile	missense_variant	2/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FPGT	ENST00000370898.9	c.118G>A	p.Val40Ile	missense_variant	2/4	1	NM_003838.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.118G>A (p.V40I) alteration is located in exon 2 (coding exon 2) of the FPGT gene. This alteration results from a G to A substitution at nucleotide position 118, causing the valine (V) at amino acid position 40 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.070
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D;T;D;D;D;T;T;T;D;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	.;.;L;.;L;.;.;.;.;.;.
MutationTaster	Benign	0.58	D;D;D;D;N;N;N;N
PROVEAN	Benign	-0.75	.;.;N;N;N;N;.;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.23	.;.;T;T;D;T;.;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;T;T;D;T;D
Vest4		0.36
MutPred		0.60		.;.;Loss of catalytic residue at V40 (P = 0.0779);.;Loss of catalytic residue at V40 (P = 0.0779);.;.;Loss of catalytic residue at V40 (P = 0.0779);Loss of catalytic residue at V40 (P = 0.0779);Loss of catalytic residue at V40 (P = 0.0779);Loss of catalytic residue at V40 (P = 0.0779);
MVP		0.28
MPC		0.021
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.025
gMVP		0.19

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: rs1428899793; hg19: chr1-74665383;