1-74198309-T-C

Variant names:

• chr1-74198309-T-C
• NM_003838.5:c.31T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003838.5(FPGT):​c.31T>C​(p.Ser11Pro) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FPGT NM_003838.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.01
• 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]

LRRIQ3 (HGNC:28318): (leucine rich repeats and IQ motif containing 3)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082829684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGT	NM_003838.5	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 4	ENST00000370898.9	NP_003829.4
LRRIQ3	NM_001105659.2	c.-314A>G		upstream_gene_variant		ENST00000354431.9	NP_001099129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGT	ENST00000370898.9	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 4	1	NM_003838.5	ENSP00000359935.4
FPGT-TNNI3K	ENST00000557284.7	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 27	2		ENSP00000450895.3
LRRIQ3	ENST00000354431.9	c.-314A>G		upstream_gene_variant		5	NM_001105659.2	ENSP00000346414.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70T>C (p.S24P) alteration is located in exon 1 (coding exon 1) of the FPGT-TNNI3K gene. This alteration results from a T to C substitution at nucleotide position 70, causing the serine (S) at amino acid position 24 to be replaced by a proline (P). 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	0.11
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	3.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.;.;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.56	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;L;.;L;.;.;.;.;.
PhyloP100		-1.0
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.13	T;T;D;T;T;D;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T;T
Vest4		0.29
MutPred		0.17		.;.;Loss of phosphorylation at S11 (P = 0.0069);Loss of phosphorylation at S11 (P = 0.0069);Loss of phosphorylation at S11 (P = 0.0069);.;Loss of phosphorylation at S11 (P = 0.0069);Loss of phosphorylation at S11 (P = 0.0069);Loss of phosphorylation at S11 (P = 0.0069);Loss of phosphorylation at S11 (P = 0.0069);
MVP		0.47
MPC		0.025
ClinPred		0.077	T
GERP RS		-3.4
PromoterAI		0.0038	Neutral
Varity_R		0.13
gMVP		0.34
Mutation Taster		=90/10	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

hg19: chr1-74663993;