2-187467924-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006287.6(TFPI):c.637G>A(p.Gly213Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000418 in 1,410,082 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000042 ( 0 hom. )

Consequence

TFPI
NM_006287.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.206

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12764743).

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.637G>A	p.Gly213Ser	missense	Exon 7 of 8	NP_006278.1	P10646-1
TFPI	NM_001329239.2		c.637G>A	p.Gly213Ser	missense	Exon 9 of 10	NP_001316168.1	P10646-1
TFPI	NM_001329240.2		c.637G>A	p.Gly213Ser	missense	Exon 8 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.637G>A	p.Gly213Ser	missense	Exon 7 of 8	ENSP00000233156.3	P10646-1
TFPI	ENST00000392365.5	TSL:5	c.637G>A	p.Gly213Ser	missense	Exon 7 of 8	ENSP00000376172.1	P10646-1
TFPI	ENST00000897898.1		c.637G>A	p.Gly213Ser	missense	Exon 8 of 9	ENSP00000567957.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000186

AC:

AN:

215530

AF XY:

0.0000255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000418

AC:

AN:

1410082

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

699742

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31546

American (AMR)

AF:

0.00

AC:

AN:

34966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23828

East Asian (EAS)

AF:

0.00

AC:

AN:

38348

South Asian (SAS)

AF:

0.0000260

AC:

AN:

76928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

0.0000514

AC:

AN:

1089096

Other (OTH)

AF:

0.0000173

AC:

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000671

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

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

0.17

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.25

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.71

M_CAP

Benign

0.034

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.8

PhyloP100

-0.21

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.6

REVEL

Benign

0.11

Sift

Benign

0.32

Sift4G

Benign

0.31

Polyphen

0.99

Vest4

0.12

MutPred

0.36

Loss of catalytic residue at G213 (P = 0.0705)

MVP

0.64

MPC

0.62

ClinPred

0.10

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.59

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over