Variant 2-187466977-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_006287.6(TFPI):c.874G>A(p.Val292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,583,820 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.014 ( 17 hom., cov: 32)

Exomes 𝑓: 0.018 ( 326 hom. )

Consequence

TFPI
NM_006287.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.670

Variant links:

Genes affected

TFPI (HGNC:11760): (tissue factor pathway inhibitor) This gene encodes a Kunitz-type serine protease inhibitor that regulates the tissue factor (TF)-dependent pathway of blood coagulation. The coagulation process initiates with the formation of a factor VIIa-TF complex, which proteolytically activates additional proteases (factors IX and X) and ultimately leads to the formation of a fibrin clot. The product of this gene inhibits the activated factor X and VIIa-TF proteases in an autoregulatory loop. Inhibition of the encoded protein restores hemostasis in animal models of hemophilia. This gene encodes multiple protein isoforms that differ in their inhibitory activity, specificity and cellular localization. [provided by RefSeq, Jul 2016]

TFPI links:

CALCRL-AS1 (HGNC:):

CALCRL-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048422813).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (2169/152036) while in subpopulation NFE AF= 0.0229 (1555/67874). AF 95% confidence interval is 0.022. There are 17 homozygotes in gnomad4. There are 990 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPI	NM_006287.6 linkuse as main transcript	c.874G>A	p.Val292Met	missense_variant	8/8	ENST00000233156.9	NP_006278.1	P10646-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9 linkuse as main transcript	c.874G>A	p.Val292Met	missense_variant	8/8	1	NM_006287.6	ENSP00000233156.3		P10646-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2167

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.00322

Gnomad MID

AF:

0.0163

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.0187

GnomAD3 exomes

AF:

0.0128

AC:

3033

AN:

237362

Hom.:

AF XY:

0.0132

AC XY:

1697

AN XY:

128850

show subpopulations

Gnomad AFR exome

AF:

0.00327

Gnomad AMR exome

AF:

0.00819

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00587

Gnomad FIN exome

AF:

0.00388

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0179

AC:

25697

AN:

1431784

Hom.:

326

Cov.:

AF XY:

0.0177

AC XY:

12640

AN XY:

712320

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.00913

Gnomad4 ASJ exome

AF:

0.0154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00551

Gnomad4 FIN exome

AF:

0.00427

Gnomad4 NFE exome

AF:

0.0210

Gnomad4 OTH exome

AF:

0.0166

GnomAD4 genome

AF:

0.0143

AC:

2169

AN:

152036

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

990

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00429

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00766

Gnomad4 FIN

AF:

0.00322

Gnomad4 NFE

AF:

0.0229

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0210

Hom.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0246

AC:

ESP6500AA

AF:

0.00417

AC:

ESP6500EA

AF:

0.0223

AC:

188

ExAC

AF:

0.0128

AC:

1549

Asia WGS

AF:

0.00263

AC:

AN:

3438

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.64

.;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.065

Sift

Benign

0.090

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.80

P;P

Vest4

0.12

MPC

0.54

ClinPred

0.0018

GERP RS

2.0

Varity_R

0.023

gMVP

0.43

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over