Variant chr2-187478770-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000339091.8(TFPI):c.662A>G(p.Asn221Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,612,272 control chromosomes in the GnomAD database, including 72,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7567 hom., cov: 32)

Exomes 𝑓: 0.29 ( 65023 hom. )

Consequence

TFPI
ENST00000339091.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.75

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:55863): (CALCRL and TFPI antisense RNA 1)

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=0.003328681).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPI	NM_006287.6 linkuse as main transcript	c.628+5354A>G		intron_variant		ENST00000233156.9	NP_006278.1
CALCRL-AS1	XR_007087504.1 linkuse as main transcript	n.3420-20736T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9 linkuse as main transcript	c.628+5354A>G		intron_variant		1	NM_006287.6	ENSP00000233156	P1	P10646-1
CALCRL-AS1	ENST00000412276.6 linkuse as main transcript	n.190-20736T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47230

AN:

151954

Hom.:

7559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.355

Gnomad AMI

AF:

0.310

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.312

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.285

AC:

71467

AN:

250532

Hom.:

10773

AF XY:

0.291

AC XY:

39345

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.355

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.331

Gnomad EAS exome

AF:

0.139

Gnomad SAS exome

AF:

0.295

Gnomad FIN exome

AF:

0.304

Gnomad NFE exome

AF:

0.317

Gnomad OTH exome

AF:

0.306

GnomAD4 exome

AF:

0.295

AC:

430416

AN:

1460200

Hom.:

65023

Cov.:

AF XY:

0.296

AC XY:

215289

AN XY:

726432

show subpopulations

Gnomad4 AFR exome

AF:

0.363

Gnomad4 AMR exome

AF:

0.198

Gnomad4 ASJ exome

AF:

0.334

Gnomad4 EAS exome

AF:

0.101

Gnomad4 SAS exome

AF:

0.297

Gnomad4 FIN exome

AF:

0.308

Gnomad4 NFE exome

AF:

0.301

Gnomad4 OTH exome

AF:

0.304

GnomAD4 genome

AF:

0.311

AC:

47267

AN:

152072

Hom.:

7567

Cov.:

AF XY:

0.308

AC XY:

22869

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.355

Gnomad4 AMR

AF:

0.256

Gnomad4 ASJ

AF:

0.331

Gnomad4 EAS

AF:

0.135

Gnomad4 SAS

AF:

0.288

Gnomad4 FIN

AF:

0.299

Gnomad4 NFE

AF:

0.312

Gnomad4 OTH

AF:

0.329

Alfa

AF:

0.302

Hom.:

12588

Bravo

AF:

0.308

TwinsUK

AF:

0.279

AC:

1036

ALSPAC

AF:

0.289

AC:

1113

ESP6500AA

AF:

0.347

AC:

1528

ESP6500EA

AF:

0.310

AC:

2670

ExAC

AF:

0.293

AC:

35532

Asia WGS

AF:

0.253

AC:

876

AN:

3476

EpiCase

AF:

0.320

EpiControl

AF:

0.316

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.57

.;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P;P;P

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.12

Sift

Benign

0.47

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.19

B;B

Vest4

0.077

ClinPred

0.0051

GERP RS

3.6

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