rs7586970

Variant names:

• chr2-187478770-T-C
• rs7586970
• ENST00000339091.8:c.662A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-187478770-T-C
• chr2-187478770-T-G

Variant summary

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

The NM_001032281.4(TFPI):​c.662A>G​(p.Asn221Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,612,272 control chromosomes in the GnomAD database, including 72,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (7567 hom., cov: 32)
  • Exomes 𝑓: 0.29 (65023 hom.)
• Consequence: TFPI NM_001032281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 57 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 (MetaRNN=0.003328681).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032281.4. 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.628+5354A>G		intron	N/A	NP_006278.1
	TFPI	NM_001032281.4		c.662A>G	p.Asn221Ser	missense	Exon 7 of 7	NP_001027452.1
	TFPI	NM_001318941.3		c.662A>G	p.Asn221Ser	missense	Exon 8 of 8	NP_001305870.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI	ENST00000339091.8	TSL:1	c.662A>G	p.Asn221Ser	missense	Exon 7 of 7	ENSP00000342306.4
	TFPI	ENST00000409676.5	TSL:1	c.662A>G	p.Asn221Ser	missense	Exon 8 of 8	ENSP00000386344.1
	TFPI	ENST00000233156.9	TSL:1 MANE Select	c.628+5354A>G		intron	N/A	ENSP00000233156.3

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47230 AN: 151954 Hom.: 7559 Cov.: 32

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.285 AC: 71467 AN: 250532 AF XY: 0.291

Gnomad AFR exome AF: 0.355

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.295 AC: 430416 AN: 1460200 Hom.: 65023 Cov.: 34 AF XY: 0.296 AC XY: 215289 AN XY: 726432

African (AFR) AF: 0.363 AC: 12133 AN: 33446

American (AMR) AF: 0.198 AC: 8864 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8722 AN: 26118

East Asian (EAS) AF: 0.101 AC: 4017 AN: 39608

South Asian (SAS) AF: 0.297 AC: 25567 AN: 86178

European-Finnish (FIN) AF: 0.308 AC: 16407 AN: 53328

Middle Eastern (MID) AF: 0.388 AC: 2181 AN: 5614

European-Non Finnish (NFE) AF: 0.301 AC: 334200 AN: 1110892

Other (OTH) AF: 0.304 AC: 18325 AN: 60322

GnomAD4 genome AF: 0.311 AC: 47267 AN: 152072 Hom.: 7567 Cov.: 32 AF XY: 0.308 AC XY: 22869 AN XY: 74346

African (AFR) AF: 0.355 AC: 14708 AN: 41482

American (AMR) AF: 0.256 AC: 3914 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3472

East Asian (EAS) AF: 0.135 AC: 701 AN: 5186

South Asian (SAS) AF: 0.288 AC: 1388 AN: 4822

European-Finnish (FIN) AF: 0.299 AC: 3156 AN: 10568

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21173 AN: 67962

Other (OTH) AF: 0.329 AC: 694 AN: 2110

Alfa AF: 0.305 Hom.: 26244

Bravo AF: 0.308

TwinsUK AF: 0.279 AC: 1036

ALSPAC AF: 0.289 AC: 1113

ESP6500AA AF: 0.347 AC: 1528

ESP6500EA AF: 0.310 AC: 2670

ExAC AF: 0.293 AC: 35532

Asia WGS AF: 0.253 AC: 876 AN: 3476

EpiCase AF: 0.320

EpiControl AF: 0.316

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.8
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.12
Sift	Benign	0.47	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.19	B
Vest4		0.077
ClinPred		0.0051	T
GERP RS		3.6
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: rs7586970; hg19: chr2-188343497; COSMIC: COSV51899575;