Genetic Variant NM_006287.6:c.629-33T>C (chr2-187467965-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006287.6(TFPI):c.629-33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,511,534 control chromosomes in the GnomAD database, including 69,989 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 8387 hom., cov: 31)

Exomes 𝑓: 0.30 ( 61602 hom. )

Consequence

TFPI
NM_006287.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0900

Publications

19 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 (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006287.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFPI	NM_006287.6	MANE Select	c.629-33T>C	intron	N/A	NP_006278.1	P10646-1
TFPI	NM_001329239.2		c.629-33T>C	intron	N/A	NP_001316168.1	P10646-1
TFPI	NM_001329240.2		c.629-33T>C	intron	N/A	NP_001316169.1	P10646-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFPI	ENST00000233156.9	TSL:1 MANE Select	c.629-33T>C	intron	N/A	ENSP00000233156.3	P10646-1
TFPI	ENST00000392365.5	TSL:5	c.629-33T>C	intron	N/A	ENSP00000376172.1	P10646-1
TFPI	ENST00000897898.1		c.629-33T>C	intron	N/A	ENSP00000567957.1

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49480

AN:

151818

Hom.:

8379

Cov.:

show subpopulations

Gnomad AFR

AF:

0.404

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.349

Gnomad NFE

AF:

0.312

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.300

AC:

57055

AN:

189948

AF XY:

0.304

show subpopulations

Gnomad AFR exome

AF:

0.412

Gnomad AMR exome

AF:

0.208

Gnomad ASJ exome

AF:

0.342

Gnomad EAS exome

AF:

0.142

Gnomad FIN exome

AF:

0.307

Gnomad NFE exome

AF:

0.322

Gnomad OTH exome

AF:

0.319

GnomAD4 exome

AF:

0.298

AC:

405613

AN:

1359600

Hom.:

61602

Cov.:

AF XY:

0.300

AC XY:

201109

AN XY:

670948

show subpopulations

African (AFR)

AF:

0.413

AC:

12609

AN:

30510

American (AMR)

AF:

0.218

AC:

6536

AN:

30036

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

7131

AN:

21274

East Asian (EAS)

AF:

0.0999

AC:

3756

AN:

37596

South Asian (SAS)

AF:

0.300

AC:

20199

AN:

67222

European-Finnish (FIN)

AF:

0.309

AC:

15335

AN:

49692

Middle Eastern (MID)

AF:

0.398

AC:

2138

AN:

5366

European-Non Finnish (NFE)

AF:

0.302

AC:

320611

AN:

1062172

Other (OTH)

AF:

0.310

AC:

17298

AN:

55732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

14155

28310

42464

56619

70774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10724

21448

32172

42896

53620

<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:

0.326

AC:

49518

AN:

151934

Hom.:

8387

Cov.:

AF XY:

0.322

AC XY:

23876

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.403

AC:

16709

AN:

41452

American (AMR)

AF:

0.268

AC:

4074

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1150

AN:

3470

East Asian (EAS)

AF:

0.135

AC:

700

AN:

5178

South Asian (SAS)

AF:

0.289

AC:

1389

AN:

4808

European-Finnish (FIN)

AF:

0.299

AC:

3151

AN:

10540

Middle Eastern (MID)

AF:

0.352

AC:

102

AN:

290

European-Non Finnish (NFE)

AF:

0.312

AC:

21228

AN:

67956

Other (OTH)

AF:

0.347

AC:

732

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1691

3382

5073

6764

8455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.319

Hom.:

21380

Bravo

AF:

0.326

Asia WGS

AF:

0.256

AC:

890

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.12

(source)

DANN

Benign

0.28

PhyloP100

0.090

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over