Variant 1-94536123-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001993.5(F3):c.254C>T(p.Thr85Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

F3
NM_001993.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.750

Variant links:

Genes affected

F3 (HGNC:3541): (coagulation factor III, tissue factor) This gene encodes coagulation factor III which is a cell surface glycoprotein. This factor enables cells to initiate the blood coagulation cascades, and it functions as the high-affinity receptor for the coagulation factor VII. The resulting complex provides a catalytic event that is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Unlike the other cofactors of these protease cascades, which circulate as nonfunctional precursors, this factor is a potent initiator that is fully functional when expressed on cell surfaces, for example, on monocytes. There are 3 distinct domains of this factor: extracellular, transmembrane, and cytoplasmic. Platelets and monocytes have been shown to express this coagulation factor under procoagulatory and proinflammatory stimuli, and a major role in HIV-associated coagulopathy has been described. Platelet-dependent monocyte expression of coagulation factor III has been described to be associated with Coronavirus Disease 2019 (COVID-19) severity and mortality. This protein is the only one in the coagulation pathway for which a congenital deficiency has not been described. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Aug 2020]

F3 links:

F3 (HGNC:):

F3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F3	NM_001993.5 linkuse as main transcript	c.254C>T	p.Thr85Ile	missense_variant	3/6	ENST00000334047.12	NP_001984.1	P13726-1
F3	NM_001178096.2 linkuse as main transcript	c.254C>T	p.Thr85Ile	missense_variant	3/5		NP_001171567.1	P13726-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F3	ENST00000334047.12 linkuse as main transcript	c.254C>T	p.Thr85Ile	missense_variant	3/6	1	NM_001993.5	ENSP00000334145.7	P13726-1
F3	ENST00000370207.4 linkuse as main transcript	c.254C>T	p.Thr85Ile	missense_variant	3/5	1		ENSP00000359226.4	P13726-2
F3	ENST00000478217.5 linkuse as main transcript	n.42C>T		non_coding_transcript_exon_variant	1/2	3
F3	ENST00000480356.1 linkuse as main transcript	n.872C>T		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251472

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.254C>T (p.T85I) alteration is located in exon 3 (coding exon 3) of the F3 gene. This alteration results from a C to T substitution at nucleotide position 254, causing the threonine (T) at amino acid position 85 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

0.26

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

0.11

Eigen_PC

Benign

-0.081

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.022

D;D

Sift4G

Uncertain

0.038

D;D

Polyphen

0.98

D;D

Vest4

0.26

MutPred

0.63

Loss of ubiquitination at K80 (P = 0.0504);Loss of ubiquitination at K80 (P = 0.0504);

MVP

0.86

MPC

0.51

ClinPred

0.71

GERP RS

4.5

Varity_R

0.36

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over