chr1-74199727-A-G

Position:

• chr1-74199727-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003838.5(FPGT):​c.146A>G​(p.Gln49Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FPGT NM_003838.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FPGT	NM_003838.5	c.146A>G	p.Gln49Arg	missense_variant	2/4	ENST00000370898.9	NP_003829.4
FPGT-TNNI3K	NM_001112808.3	c.146A>G	p.Gln49Arg	missense_variant	2/27		NP_001106279.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FPGT	ENST00000370898.9	c.146A>G	p.Gln49Arg	missense_variant	2/4	1	NM_003838.5	ENSP00000359935	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Apr 18, 2023

The c.185A>G (p.K62R) alteration is located in exon 2 (coding exon 2) of the FPGT-TNNI3K gene. This alteration results from a A to G substitution at nucleotide position 185, causing the lysine (K) at amino acid position 62 to be replaced by an arginine (R). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;M;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;N;N
PROVEAN	Uncertain	-3.7	.;.;D;D;D;D;.;N;N;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	.;.;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.87
MutPred		0.65		.;.;Gain of ubiquitination at K48 (P = 0.1222);.;Gain of ubiquitination at K48 (P = 0.1222);.;.;Gain of ubiquitination at K48 (P = 0.1222);Gain of ubiquitination at K48 (P = 0.1222);Gain of ubiquitination at K48 (P = 0.1222);Gain of ubiquitination at K48 (P = 0.1222);
MVP		0.93
MPC		0.093
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-74665411;