Genetic Variant TFPI2:p.Ser10* (chr7-93890650-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006528.4(TFPI2):c.29C>A(p.Ser10*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TFPI2
NM_006528.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.287

Publications

0 publications found

Variant links:

Genes affected

TFPI2 (HGNC:11761): (tissue factor pathway inhibitor 2) This gene encodes a member of the Kunitz-type serine proteinase inhibitor family. The protein can inhibit a variety of serine proteases including factor VIIa/tissue factor, factor Xa, plasmin, trypsin, chymotryspin and plasma kallikrein. This gene has been identified as a tumor suppressor gene in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

TFPI2 links:

GNGT1 (HGNC:4411): (G protein subunit gamma transducin 1) This gene encodes the gamma subunit of transducin, a guanine nucleotide-binding protein (G protein) that is found in rod outer segments. Transducin, also known as GMPase, mediates the activation of a cyclic GTP-specific (guanosine monophosphate) phosphodiesterase by rhodopsin. [provided by RefSeq, Jul 2016]

GNGT1 links:

TFPI2-DT (HGNC:40581): (TFPI2 divergent transcript)

TFPI2-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006528.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFPI2	NM_006528.4	MANE Select	c.29C>A	p.Ser10*	stop_gained	Exon 1 of 5	NP_006519.1	P48307-1
TFPI2	NM_001271003.2		c.29C>A	p.Ser10*	stop_gained	Exon 1 of 5	NP_001257932.1	P48307-2
TFPI2	NM_001271004.2		c.29C>A	p.Ser10*	stop_gained	Exon 1 of 5	NP_001257933.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFPI2	ENST00000222543.11	TSL:1 MANE Select	c.29C>A	p.Ser10*	stop_gained	Exon 1 of 5	ENSP00000222543.5	P48307-1
TFPI2	ENST00000650573.1		c.29C>A	p.Ser10*	stop_gained	Exon 1 of 5	ENSP00000497131.1	A0A3B3IS67
TFPI2	ENST00000898459.1		c.29C>A	p.Ser10*	stop_gained	Exon 1 of 4	ENSP00000568518.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460924

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111762

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.025

PhyloP100

-0.29

Vest4

0.29

GERP RS

-1.4

PromoterAI

-0.039

Neutral

(source)

Mutation Taster

=26/174

disease causing (fs/PTC)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over