rs4667168

Positions:

• chr2-187528213-G-A
• chr2-187528213-G-T

Variant summary

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

The NM_006287.6(TFPI):​c.-2-24443C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 151,986 control chromosomes in the GnomAD database, including 3,525 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 0.19 (3525 hom., cov: 32)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370

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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPI	NM_006287.6	c.-2-24443C>T		intron_variant		ENST00000233156.9	NP_006278.1
CALCRL-AS1	XR_007087504.1	n.3520-18516G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.-2-24443C>T		intron_variant		1	NM_006287.6	ENSP00000233156	P1
CALCRL-AS1	ENST00000412276.6	n.290-18516G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28197 AN: 151866 Hom.: 3517 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.0994

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.186 AC: 28242 AN: 151986 Hom.: 3525 Cov.: 32 AF XY: 0.189 AC XY: 14021 AN XY: 74294

Gnomad4 AFR AF: 0.336

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.0994

Gnomad4 NFE AF: 0.0929

Gnomad4 OTH AF: 0.178

Alfa AF: 0.0402 Hom.: 37

Bravo AF: 0.201

Asia WGS AF: 0.261 AC: 907 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.7
DANN	Benign	0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4667168; hg19: chr2-188392940;