2-187484906-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006287.6(TFPI):c.440C>A(p.Thr147Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,588,708 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (17 hom.)
• Consequence: TFPI NM_006287.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.57

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006154537).
• BP6: Variant 2-187484906-G-T is Benign according to our data. Variant chr2-187484906-G-T is described in ClinVar as [Benign]. Clinvar id is 775182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFPI	NM_006287.6	c.440C>A	p.Thr147Lys	missense_variant	5/8	ENST00000233156.9
CALCRL-AS1	XR_007087504.1	n.3420-14600G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFPI	ENST00000233156.9	c.440C>A	p.Thr147Lys	missense_variant	5/8	1	NM_006287.6	P1
CALCRL-AS1	ENST00000412276.6	n.190-14600G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 151728 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000725

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00194 AC: 454 AN: 233666 Hom.: 4 AF XY: 0.00262 AC XY: 332 AN XY: 126728

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.000907

Gnomad ASJ exome AF: 0.00256

Gnomad EAS exome AF: 0.0000592

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000736

GnomAD4 exome AF: 0.00172 AC: 2473 AN: 1436862 Hom.: 17 Cov.: 30 AF XY: 0.00207 AC XY: 1474 AN XY: 713062

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.000905

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00115 AC: 174 AN: 151846 Hom.: 0 Cov.: 32 AF XY: 0.00135 AC XY: 100 AN XY: 74230

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000724

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000869

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.00232 AC: 282

Asia WGS AF: 0.00404 AC: 14 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.35	T;T;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0062	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D;D;D;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D;D;T;T
Sift4G	Uncertain	0.0030	D;D;.;D;D
Polyphen		0.0040	B;B;.;B;B
Vest4		0.24
MVP		0.70
MPC		0.71
ClinPred		0.069	T
GERP RS		5.9
Varity_R		0.30
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs145362964; hg19: chr2-188349633;