dbSNP rs6434222: TFPI:c.-3+6683A>T (chr2-187547517-T-A) – 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.-3+6683A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,036 control chromosomes in the GnomAD database, including 3,606 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 0.20 ( 3606 hom., cov: 31)

Exomes 𝑓: 0.10 ( 0 hom. )

Consequence

TFPI
NM_006287.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.49

Publications

7 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=-0.73).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFPI	NM_006287.6 link	c.-3+6683A>T		intron_variant	Intron 1 of 7	ENST00000233156.9	NP_006278.1	P10646-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9 link	c.-3+6683A>T		intron_variant	Intron 1 of 7	1	NM_006287.6	ENSP00000233156.3		P10646-1

Frequencies

GnomAD3 genomes

AF:

0.195

AC:

29621

AN:

151908

Hom.:

3604

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.169

Gnomad EAS

AF:

0.314

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.199

GnomAD4 exome

AF:

0.100

AC:

AN:

Hom.:

Cov.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.100

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.195

AC:

29655

AN:

152026

Hom.:

3606

Cov.:

AF XY:

0.198

AC XY:

14716

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.322

AC:

13328

AN:

41442

American (AMR)

AF:

0.231

AC:

3519

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

585

AN:

3470

East Asian (EAS)

AF:

0.315

AC:

1620

AN:

5150

South Asian (SAS)

AF:

0.218

AC:

1052

AN:

4822

European-Finnish (FIN)

AF:

0.105

AC:

1116

AN:

10588

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7808

AN:

67970

Other (OTH)

AF:

0.198

AC:

419

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1129

2258

3386

4515

5644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.152

Hom.:

299

Bravo

AF:

0.208

Asia WGS

AF:

0.268

AC:

932

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

2.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over