1-94536099-T-C

Position:

chr1-94536099-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001993.5(F3):c.278A>G(p.Asp93Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000997 in 1,614,120 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0049 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 10 hom. )

Consequence

F3
NM_001993.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.79

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011745065).

BP6

Variant 1-94536099-T-C is Benign according to our data. Variant chr1-94536099-T-C is described in ClinVar as [Benign]. Clinvar id is 715332.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00491 (748/152262) while in subpopulation AFR AF= 0.0166 (688/41552). AF 95% confidence interval is 0.0155. There are 4 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F3	NM_001993.5 linkuse as main transcript	c.278A>G	p.Asp93Gly	missense_variant	3/6	ENST00000334047.12	NP_001984.1
F3	NM_001178096.2 linkuse as main transcript	c.278A>G	p.Asp93Gly	missense_variant	3/5		NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12 linkuse as main transcript	c.278A>G	p.Asp93Gly	missense_variant	3/6	1	NM_001993.5	ENSP00000334145	P1	P13726-1
F3	ENST00000370207.4 linkuse as main transcript	c.278A>G	p.Asp93Gly	missense_variant	3/5	1		ENSP00000359226		P13726-2
F3	ENST00000478217.5 linkuse as main transcript	n.66A>G		non_coding_transcript_exon_variant	1/2	3
F3	ENST00000480356.1 linkuse as main transcript	n.896A>G		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

AF:

0.00491

AC:

747

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00153

AC:

384

AN:

251488

Hom.:

AF XY:

0.00111

AC XY:

151

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0186

Gnomad AMR exome

AF:

0.00173

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:

0.000132

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000590

AC:

862

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

391

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0166

Gnomad4 AMR exome

AF:

0.00183

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:

0.000120

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.00491

AC:

748

AN:

152262

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

334

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0166

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000751

Hom.:

Bravo

AF:

0.00594

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00183

AC:

222

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

0.035

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.012

D;T

Sift4G

Benign

0.17

T;T

Polyphen

0.99

D;D

Vest4

0.53

MVP

0.86

MPC

1.0

ClinPred

0.027

GERP RS

4.4

Varity_R

0.51

gMVP

0.83

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