chr1-94533194-G-A

Position:

chr1-94533194-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001993.5(F3):c.487C>T(p.Arg163Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,870 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

F3
NM_001993.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.540

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008093327).

BP6

Variant 1-94533194-G-A is Benign according to our data. Variant chr1-94533194-G-A is described in ClinVar as [Benign]. Clinvar id is 708858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 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.487C>T	p.Arg163Trp	missense_variant	4/6	ENST00000334047.12	NP_001984.1
F3	NM_001178096.2 linkuse as main transcript	c.487C>T	p.Arg163Trp	missense_variant	4/5		NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12 linkuse as main transcript	c.487C>T	p.Arg163Trp	missense_variant	4/6	1	NM_001993.5	ENSP00000334145	P1	P13726-1
F3	ENST00000370207.4 linkuse as main transcript	c.487C>T	p.Arg163Trp	missense_variant	4/5	1		ENSP00000359226		P13726-2
F3	ENST00000478217.5 linkuse as main transcript	n.275C>T		non_coding_transcript_exon_variant	2/2	3
F3	ENST00000480356.1 linkuse as main transcript	n.1105C>T		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

200

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0143

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000896

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00197

AC:

495

AN:

251038

Hom.:

AF XY:

0.00190

AC XY:

258

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.0118

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00124

AC:

1819

AN:

1461586

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

894

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.00970

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000952

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00131

AC:

199

AN:

152284

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.0143

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.00158

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0081

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.053

Sift

Benign

0.19

T;T

Sift4G

Benign

0.10

T;D

Polyphen

0.051

B;D

Vest4

0.19

MVP

0.62

MPC

0.29

ClinPred

0.017

GERP RS

2.3

Varity_R

0.21

gMVP

0.67

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