Genetic Variant TFPI:p.Ile272Val (chr2-187467037-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006287.6(TFPI):c.814A>G(p.Ile272Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TFPI
NM_006287.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0110

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05633083).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
TFPI	NM_006287.6	MANE Select	c.814A>G	p.Ile272Val	missense	Exon 8 of 8	NP_006278.1	P10646-1
TFPI	NM_001329239.2		c.814A>G	p.Ile272Val	missense	Exon 10 of 10	NP_001316168.1	P10646-1
TFPI	NM_001329240.2		c.814A>G	p.Ile272Val	missense	Exon 9 of 9	NP_001316169.1	P10646-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFPI	ENST00000233156.9	TSL:1 MANE Select	c.814A>G	p.Ile272Val	missense	Exon 8 of 8	ENSP00000233156.3	P10646-1
TFPI	ENST00000392365.5	TSL:5	c.814A>G	p.Ile272Val	missense	Exon 8 of 8	ENSP00000376172.1	P10646-1
TFPI	ENST00000897898.1		c.814A>G	p.Ile272Val	missense	Exon 9 of 9	ENSP00000567957.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406486

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700910

African (AFR)

AF:

0.00

AC:

AN:

31770

American (AMR)

AF:

0.00

AC:

AN:

40608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25224

East Asian (EAS)

AF:

0.00

AC:

AN:

38294

South Asian (SAS)

AF:

0.00

AC:

AN:

81108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073252

Other (OTH)

AF:

0.00

AC:

AN:

58094

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.9

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.20

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.45

M_CAP

Benign

0.014

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.011

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.26

REVEL

Benign

0.013

Sift

Benign

0.22

Sift4G

Benign

0.55

Polyphen

0.13

Vest4

0.087

MutPred

0.30

Gain of loop (P = 0.0166)

MVP

0.32

MPC

0.35

ClinPred

0.051

GERP RS

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.021

gMVP

0.31

Mutation Taster

=96/4

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over