2-187476320-G-A

Variant names:

• chr2-187476320-G-A
• rs8176541
• NM_006287.6:c.628+7804C>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.628+7804C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,002 control chromosomes in the GnomAD database, including 5,513 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 0.26 (5513 hom., cov: 31)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0360
• Publications: 8 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI	NM_006287.6	MANE Select	c.628+7804C>T		intron	N/A	NP_006278.1
	TFPI	NM_001329239.2		c.628+7804C>T		intron	N/A	NP_001316168.1
	TFPI	NM_001329240.2		c.628+7804C>T		intron	N/A	NP_001316169.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI	ENST00000233156.9	TSL:1 MANE Select	c.628+7804C>T		intron	N/A	ENSP00000233156.3
	TFPI	ENST00000392365.5	TSL:5	c.628+7804C>T		intron	N/A	ENSP00000376172.1
	TFPI	ENST00000435414.5	TSL:5	c.589+7804C>T		intron	N/A	ENSP00000409177.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39734 AN: 151884 Hom.: 5504 Cov.: 31

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.262 AC: 39766 AN: 152002 Hom.: 5513 Cov.: 31 AF XY: 0.259 AC XY: 19269 AN XY: 74302

African (AFR) AF: 0.184 AC: 7643 AN: 41456

American (AMR) AF: 0.237 AC: 3627 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1147 AN: 3468

East Asian (EAS) AF: 0.135 AC: 699 AN: 5172

South Asian (SAS) AF: 0.287 AC: 1380 AN: 4808

European-Finnish (FIN) AF: 0.299 AC: 3163 AN: 10566

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.311 AC: 21121 AN: 67948

Other (OTH) AF: 0.289 AC: 608 AN: 2104

Alfa AF: 0.296 Hom.: 9262

Bravo AF: 0.250

Asia WGS AF: 0.242 AC: 840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.85
DANN	Benign	0.23
PhyloP100		0.036
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: rs8176541; hg19: chr2-188341047;