rs8176612

Variant names:

• chr2-187484418-G-A
• rs8176612
• NM_006287.6:c.536-202C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006287.6(TFPI):​c.536-202C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 555,404 control chromosomes in the GnomAD database, including 647 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 0.037 (164 hom., cov: 32)
  • Exomes 𝑓: 0.043 (483 hom.)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 2 publications found

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]

CALCRL-AS1 (HGNC:55863): (CALCRL and TFPI antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.055 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI	NM_006287.6	MANE Select	c.536-202C>T		intron	N/A	NP_006278.1	P10646-1
	TFPI	NM_001329239.2		c.536-202C>T		intron	N/A	NP_001316168.1	P10646-1
	TFPI	NM_001329240.2		c.536-202C>T		intron	N/A	NP_001316169.1	P10646-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI	ENST00000233156.9	TSL:1 MANE Select	c.536-202C>T		intron	N/A	ENSP00000233156.3	P10646-1
	TFPI	ENST00000339091.8	TSL:1	c.536-202C>T		intron	N/A	ENSP00000342306.4	P10646-2
	TFPI	ENST00000409676.5	TSL:1	c.536-202C>T		intron	N/A	ENSP00000386344.1	P10646-2

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5594 AN: 151728 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0737

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0565

Gnomad OTH AF: 0.0537

GnomAD4 exome AF: 0.0432 AC: 17419 AN: 403558 Hom.: 483 Cov.: 4 AF XY: 0.0418 AC XY: 8876 AN XY: 212204

African (AFR) AF: 0.0103 AC: 109 AN: 10602

American (AMR) AF: 0.0303 AC: 406 AN: 13404

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 842 AN: 12752

East Asian (EAS) AF: 0.000247 AC: 7 AN: 28370

South Asian (SAS) AF: 0.0100 AC: 336 AN: 33440

European-Finnish (FIN) AF: 0.0225 AC: 626 AN: 27834

Middle Eastern (MID) AF: 0.0717 AC: 130 AN: 1812

European-Non Finnish (NFE) AF: 0.0554 AC: 13943 AN: 251454

Other (OTH) AF: 0.0427 AC: 1020 AN: 23890

GnomAD4 genome AF: 0.0368 AC: 5591 AN: 151846 Hom.: 164 Cov.: 32 AF XY: 0.0348 AC XY: 2585 AN XY: 74216

African (AFR) AF: 0.0108 AC: 450 AN: 41498

American (AMR) AF: 0.0405 AC: 616 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 255 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00934 AC: 45 AN: 4820

European-Finnish (FIN) AF: 0.0207 AC: 219 AN: 10594

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0565 AC: 3827 AN: 67794

Other (OTH) AF: 0.0527 AC: 111 AN: 2108

Alfa AF: 0.0425 Hom.: 61

Bravo AF: 0.0360

Asia WGS AF: 0.00463 AC: 18 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.083
DANN	Benign	0.29
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs8176612; hg19: chr2-188349145;