1-94530506-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001993.5(F3):c.842G>A(p.Gly281Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,614,090 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.010 ( 26 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 37 hom. )

Consequence

F3
NM_001993.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.167

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027674437).

BP6

Variant 1-94530506-C-T is Benign according to our data. Variant chr1-94530506-C-T is described in ClinVar as [Benign]. Clinvar id is 791607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1533/152222) while in subpopulation AFR AF= 0.0276 (1148/41532). AF 95% confidence interval is 0.0263. There are 26 homozygotes in gnomad4. There are 739 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F3	NM_001993.5 link	c.842G>A	p.Gly281Glu	missense_variant	Exon 6 of 6	ENST00000334047.12	NP_001984.1	P13726-1
F3	NM_001178096.2 link	c.682G>A	p.Glu228Lys	missense_variant	Exon 5 of 5		NP_001171567.1	P13726-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12 link	c.842G>A	p.Gly281Glu	missense_variant	Exon 6 of 6	1	NM_001993.5	ENSP00000334145.7		P13726-1
F3	ENST00000370207.4 link	c.682G>A	p.Glu228Lys	missense_variant	Exon 5 of 5	1		ENSP00000359226.4		P13726-2

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1532

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00386

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00959

GnomAD3 exomes

AF:

0.00650

AC:

1634

AN:

251418

Hom.:

AF XY:

0.00645

AC XY:

877

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0276

Gnomad AMR exome

AF:

0.00572

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.00734

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00734

GnomAD4 exome

AF:

0.00337

AC:

4922

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

2680

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0270

Gnomad4 AMR exome

AF:

0.00588

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.00416

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00150

Gnomad4 OTH exome

AF:

0.00641

GnomAD4 genome

AF:

0.0101

AC:

1533

AN:

152222

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

739

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0276

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00386

Gnomad4 SAS

AF:

0.0135

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00191

Gnomad4 OTH

AF:

0.00949

Alfa

AF:

0.00493

Hom.:

Bravo

AF:

0.0116

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0211

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00647

AC:

785

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00450

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.89

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.96

PROVEAN

Benign

0.80

REVEL

Benign

0.031

Sift

Pathogenic

0.0

Sift4G

Benign

0.29

Polyphen

0.017

Vest4

0.12

MVP

0.20

ClinPred

0.0080

GERP RS

2.5

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