rs8176592

Positions:

• chr2-187467965-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006287.6(TFPI):​c.629-33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,511,534 control chromosomes in the GnomAD database, including 69,989 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 0.33 (8387 hom., cov: 31)
  • Exomes 𝑓: 0.30 (61602 hom.)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0900

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPI	NM_006287.6	c.629-33T>C		intron_variant		ENST00000233156.9	NP_006278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.629-33T>C		intron_variant		1	NM_006287.6	ENSP00000233156.3

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49480 AN: 151818 Hom.: 8379 Cov.: 31

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.349

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.341

GnomAD3 exomes AF: 0.300 AC: 57055 AN: 189948 Hom.: 8814 AF XY: 0.304 AC XY: 31118 AN XY: 102522

Gnomad AFR exome AF: 0.412

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.307

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.298 AC: 405613 AN: 1359600 Hom.: 61602 Cov.: 28 AF XY: 0.300 AC XY: 201109 AN XY: 670948

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.0999

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.309

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.326 AC: 49518 AN: 151934 Hom.: 8387 Cov.: 31 AF XY: 0.322 AC XY: 23876 AN XY: 74254

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.347

Alfa AF: 0.317 Hom.: 13602

Bravo AF: 0.326

Asia WGS AF: 0.256 AC: 890 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.12
DANN	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8176592; hg19: chr2-188332692; COSMIC: COSV51901397;