rs8176612

Positions:

• chr2-187484418-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPI	NM_006287.6	c.536-202C>T		intron_variant		ENST00000233156.9	NP_006278.1
CALCRL-AS1	XR_007087504.1	n.3420-15088G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.536-202C>T		intron_variant		1	NM_006287.6	ENSP00000233156	P1
CALCRL-AS1	ENST00000412276.6	n.190-15088G>A		intron_variant, non_coding_transcript_variant		5

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

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0303

Gnomad4 ASJ exome AF: 0.0660

Gnomad4 EAS exome AF: 0.000247

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.0225

Gnomad4 NFE exome AF: 0.0554

Gnomad4 OTH exome AF: 0.0427

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

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.0737

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00934

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.0565

Gnomad4 OTH AF: 0.0527

Alfa AF: 0.0433 Hom.: 31

Bravo AF: 0.0360

Asia WGS AF: 0.00463 AC: 18 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.083
DANN	Benign	0.29

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

LitVar

Other links and lift over

dbSNP: rs8176612; hg19: chr2-188349145;