2-187494293-A-G

Variant names:

• chr2-187494293-A-G
• rs6736363
• NM_006287.6:c.319+2588T>C

Variant summary

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

The NM_006287.6(TFPI):​c.319+2588T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0656 in 151,944 control chromosomes in the GnomAD database, including 549 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 0.066 (549 hom., cov: 31)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 1 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 (EAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFPI	NM_006287.6	c.319+2588T>C		intron_variant	Intron 3 of 7	ENST00000233156.9	NP_006278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.319+2588T>C		intron_variant	Intron 3 of 7	1	NM_006287.6	ENSP00000233156.3

Frequencies

GnomAD3 genomes AF: 0.0656 AC: 9963 AN: 151826 Hom.: 547 Cov.: 31

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0594

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

GnomAD4 genome AF: 0.0656 AC: 9969 AN: 151944 Hom.: 549 Cov.: 31 AF XY: 0.0703 AC XY: 5222 AN XY: 74240

African (AFR) AF: 0.0930 AC: 3855 AN: 41434

American (AMR) AF: 0.126 AC: 1916 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3466

East Asian (EAS) AF: 0.245 AC: 1251 AN: 5114

South Asian (SAS) AF: 0.105 AC: 507 AN: 4810

European-Finnish (FIN) AF: 0.0483 AC: 510 AN: 10568

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1700 AN: 67998

Other (OTH) AF: 0.0598 AC: 126 AN: 2108

Alfa AF: 0.0162 Hom.: 10

Bravo AF: 0.0740

Asia WGS AF: 0.152 AC: 530 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.37
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs6736363; hg19: chr2-188359020; COSMIC: COSV51901852; COSMIC: COSV51901852;