chr1-74216284-A-G

Position:

• chr1-74216284-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001112808.3(FPGT-TNNI3K):​c.343+14874A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 151,502 control chromosomes in the GnomAD database, including 14,311 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (14311 hom., cov: 32)
• Consequence: FPGT-TNNI3K NM_001112808.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FPGT-TNNI3K	NM_001112808.3	c.343+14874A>G		intron_variant			NP_001106279.3
FPGT-TNNI3K	NM_001199327.2	c.343+14874A>G		intron_variant			NP_001186256.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FPGT-TNNI3K	ENST00000557284.7	c.343+14874A>G		intron_variant		2		ENSP00000450895.3

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62525 AN: 151384 Hom.: 14318 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.405

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.413 AC: 62521 AN: 151502 Hom.: 14311 Cov.: 32 AF XY: 0.418 AC XY: 30946 AN XY: 74044

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.424

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.729

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.407

Alfa AF: 0.420 Hom.: 2278

Bravo AF: 0.400

Asia WGS AF: 0.543 AC: 1891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.94
DANN	Benign	0.44

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: rs792321; hg19: chr1-74681968; COSMIC: COSV63846410;