rs6434222

chr2-187547517-T-A

Variant summary

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

The NM_006287.6(TFPI):c.-3+6683A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,036 control chromosomes in the GnomAD database, including 3,606 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 0.20 (3606 hom., cov: 31)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49

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=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFPI	NM_006287.6	c.-3+6683A>T		intron_variant		ENST00000233156.9
CALCRL-AS1	XR_007087504.1	n.4308T>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFPI	ENST00000233156.9	c.-3+6683A>T		intron_variant		1	NM_006287.6	P1
CALCRL-AS1	ENST00000412276.6	n.521T>A		non_coding_transcript_exon_variant	6/8	5

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29621 AN: 151908 Hom.: 3604 Cov.: 31

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.100 AC: 1 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 NFE exome AF: 0.100

GnomAD4 genome AF: 0.195 AC: 29655 AN: 152026 Hom.: 3606 Cov.: 31 AF XY: 0.198 AC XY: 14716 AN XY: 74304

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.198

Alfa AF: 0.152 Hom.: 299

Bravo AF: 0.208

Asia WGS AF: 0.268 AC: 932 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.71
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6434222; hg19: chr2-188412244;