rs35935664

chr2-187531609-A-C

Variant summary

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

The NM_006287.6(TFPI):c.-3+22591T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,958 control chromosomes in the GnomAD database, including 4,170 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 0.23 (4170 hom., cov: 32)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43

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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFPI	NM_006287.6	c.-3+22591T>G		intron_variant		ENST00000233156.9
CALCRL-AS1	XR_007087504.1	n.3520-15120A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFPI	ENST00000233156.9	c.-3+22591T>G		intron_variant		1	NM_006287.6	P1
CALCRL-AS1	ENST00000412276.6	n.290-15120A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34869 AN: 151840 Hom.: 4169 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.230 AC: 34893 AN: 151958 Hom.: 4170 Cov.: 32 AF XY: 0.231 AC XY: 17130 AN XY: 74282

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.235

Alfa AF: 0.254 Hom.: 649

Bravo AF: 0.218

Asia WGS AF: 0.241 AC: 830 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	3.7
Dann	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35935664; hg19: chr2-188396336;