Genetic Variant ENST00000339091.8:c.662A>G (chr2-187478770-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -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. 13/17 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

Publications

57 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TFPI	NM_006287.6 link	c.628+5354A>G		intron_variant	Intron 6 of 7	ENST00000233156.9	NP_006278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9 link	c.628+5354A>G		intron_variant	Intron 6 of 7	1	NM_006287.6	ENSP00000233156.3

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

GnomAD2 exomes

AF:

0.285

AC:

71467

AN:

250532

AF XY:

0.291

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 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

African (AFR)

AF:

0.363

AC:

12133

AN:

33446

American (AMR)

AF:

0.198

AC:

8864

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

8722

AN:

26118

East Asian (EAS)

AF:

0.101

AC:

4017

AN:

39608

South Asian (SAS)

AF:

0.297

AC:

25567

AN:

86178

European-Finnish (FIN)

AF:

0.308

AC:

16407

AN:

53328

Middle Eastern (MID)

AF:

0.388

AC:

2181

AN:

5614

European-Non Finnish (NFE)

AF:

0.301

AC:

334200

AN:

1110892

Other (OTH)

AF:

0.304

AC:

18325

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

14600

29200

43800

58400

73000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10770

21540

32310

43080

53850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.311

AC:

47267

AN:

152072

Hom.:

7567

Cov.:

AF XY:

0.308

AC XY:

22869

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.355

AC:

14708

AN:

41482

American (AMR)

AF:

0.256

AC:

3914

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1148

AN:

3472

East Asian (EAS)

AF:

0.135

AC:

701

AN:

5186

South Asian (SAS)

AF:

0.288

AC:

1388

AN:

4822

European-Finnish (FIN)

AF:

0.299

AC:

3156

AN:

10568

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.312

AC:

21173

AN:

67962

Other (OTH)

AF:

0.329

AC:

694

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1658

3317

4975

6634

8292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.305

Hom.:

26244

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

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

PhyloP100

1.8

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over