2-187505505-T-C

Variant names:

• chr2-187505505-T-C
• rs3755248
• NM_006287.6:c.-2-1735A>G

Variant summary

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

The NM_006287.6(TFPI):​c.-2-1735A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 151,978 control chromosomes in the GnomAD database, including 14,499 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 0.41 (14499 hom., cov: 32)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610
• Publications: 13 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.64 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI	NM_006287.6	MANE Select	c.-2-1735A>G		intron	N/A	NP_006278.1	P10646-1
	TFPI	NM_001329239.2		c.-2-1735A>G		intron	N/A	NP_001316168.1	P10646-1
	TFPI	NM_001329240.2		c.-2-1735A>G		intron	N/A	NP_001316169.1	P10646-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI	ENST00000233156.9	TSL:1 MANE Select	c.-2-1735A>G		intron	N/A	ENSP00000233156.3	P10646-1
	TFPI	ENST00000339091.8	TSL:1	c.-2-1735A>G		intron	N/A	ENSP00000342306.4	P10646-2
	TFPI	ENST00000409676.5	TSL:1	c.-2-1735A>G		intron	N/A	ENSP00000386344.1	P10646-2

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61988 AN: 151860 Hom.: 14463 Cov.: 32

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.393

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

GnomAD4 genome AF: 0.408 AC: 62082 AN: 151978 Hom.: 14499 Cov.: 32 AF XY: 0.405 AC XY: 30077 AN XY: 74306

African (AFR) AF: 0.646 AC: 26765 AN: 41432

American (AMR) AF: 0.293 AC: 4462 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1105 AN: 3466

East Asian (EAS) AF: 0.199 AC: 1031 AN: 5178

South Asian (SAS) AF: 0.399 AC: 1923 AN: 4820

European-Finnish (FIN) AF: 0.317 AC: 3355 AN: 10574

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22110 AN: 67954

Other (OTH) AF: 0.398 AC: 837 AN: 2104

Alfa AF: 0.356 Hom.: 34930

Bravo AF: 0.412

Asia WGS AF: 0.338 AC: 1173 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.8
DANN	Benign	0.67
PhyloP100		-0.061
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: rs3755248; hg19: chr2-188370232;