2-187504064-C-T

Position:

• chr2-187504064-C-T

Variant summary

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

The NM_006287.6(TFPI):​c.-2-294G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 151,896 control chromosomes in the GnomAD database, including 8,680 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 0.32 (8680 hom., cov: 32)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640

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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFPI	NM_006287.6	c.-2-294G>A		intron_variant		ENST00000233156.9
CALCRL-AS1	XR_007087504.1	n.3519+4459C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFPI	ENST00000233156.9	c.-2-294G>A		intron_variant		1	NM_006287.6	P1
CALCRL-AS1	ENST00000412276.6	n.289+4459C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47934 AN: 151778 Hom.: 8679 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.387

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.338

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.316 AC: 47933 AN: 151896 Hom.: 8680 Cov.: 32 AF XY: 0.310 AC XY: 23007 AN XY: 74224

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.288

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.334

Alfa AF: 0.386 Hom.: 18640

Bravo AF: 0.317

Asia WGS AF: 0.267 AC: 932 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.6
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2192824; hg19: chr2-188368791;