rs5940

Variant names:

• chr2-187466977-C-T
• rs5940
• NM_006287.6:c.874G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006287.6(TFPI):​c.874G>A​(p.Val292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,583,820 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.014 (17 hom., cov: 32)
  • Exomes 𝑓: 0.018 (326 hom.)
• Consequence: TFPI NM_006287.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.670
• Publications: 23 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=0.0048422813).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0143 (2169/152036) while in subpopulation NFE AF = 0.0229 (1555/67874). AF 95% confidence interval is 0.022. There are 17 homozygotes in GnomAd4. There are 990 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFPI	NM_006287.6	c.874G>A	p.Val292Met	missense_variant	Exon 8 of 8	ENST00000233156.9	NP_006278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.874G>A	p.Val292Met	missense_variant	Exon 8 of 8	1	NM_006287.6	ENSP00000233156.3

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2167 AN: 151920 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00322

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0128 AC: 3033 AN: 237362 AF XY: 0.0132

Gnomad AFR exome AF: 0.00327

Gnomad AMR exome AF: 0.00819

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0179 AC: 25697 AN: 1431784 Hom.: 326 Cov.: 28 AF XY: 0.0177 AC XY: 12640 AN XY: 712320

African (AFR) AF: 0.00299 AC: 97 AN: 32474

American (AMR) AF: 0.00913 AC: 384 AN: 42064

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 392 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 38346

South Asian (SAS) AF: 0.00551 AC: 457 AN: 82902

European-Finnish (FIN) AF: 0.00427 AC: 225 AN: 52694

Middle Eastern (MID) AF: 0.0296 AC: 166 AN: 5608

European-Non Finnish (NFE) AF: 0.0210 AC: 22994 AN: 1093312

Other (OTH) AF: 0.0166 AC: 982 AN: 58986

GnomAD4 genome AF: 0.0143 AC: 2169 AN: 152036 Hom.: 17 Cov.: 32 AF XY: 0.0133 AC XY: 990 AN XY: 74314

African (AFR) AF: 0.00429 AC: 178 AN: 41540

American (AMR) AF: 0.0173 AC: 264 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4832

European-Finnish (FIN) AF: 0.00322 AC: 34 AN: 10570

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.0229 AC: 1555 AN: 67874

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.0198 Hom.: 65

Bravo AF: 0.0158

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00417 AC: 18

ESP6500EA AF: 0.0223 AC: 188

ExAC AF: 0.0128 AC: 1549

Asia WGS AF: 0.00263 AC: 9 AN: 3438

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.64	.;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		0.67
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.065
Sift	Benign	0.090	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.80	P;P
Vest4		0.12
MPC		0.54
ClinPred		0.0018	T
GERP RS		2.0
Varity_R		0.023
gMVP		0.43
Mutation Taster		=99/1	polymorphism

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: rs5940; hg19: chr2-188331704; COSMIC: COSV99028490; COSMIC: COSV99028490;