2-187484906-G-T

Variant names:

• chr2-187484906-G-T
• rs145362964
• NM_006287.6:c.440C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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. 13/22 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, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -16 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_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFPI	NM_006287.6	c.440C>A	p.Thr147Lys	missense_variant	Exon 5 of 8	ENST00000233156.9	NP_006278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.440C>A	p.Thr147Lys	missense_variant	Exon 5 of 8	1	NM_006287.6	ENSP00000233156.3

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

GnomAD2 exomes AF: 0.00194 AC: 454 AN: 233666 AF XY: 0.00262

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 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 AC: 4 AN: 32152

Gnomad4 AMR exome AF: 0.000905 AC: 37 AN: 40866

Gnomad4 ASJ exome AF: 0.00264 AC: 68 AN: 25786

Gnomad4 EAS exome AF: 0.0000261 AC: 1 AN: 38246

Gnomad4 SAS exome AF: 0.0107 AC: 842 AN: 78628

Gnomad4 FIN exome AF: 0.0000376 AC: 2 AN: 53206

Gnomad4 NFE exome AF: 0.00127 AC: 1405 AN: 1102764

Gnomad4 Remaining exome AF: 0.00158 AC: 94 AN: 59494

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 AC: 0.000216888 AN: 0.000216888

Gnomad4 AMR AF: 0.000724 AC: 0.00072397 AN: 0.00072397

Gnomad4 ASJ AF: 0.00202 AC: 0.00201845 AN: 0.00201845

Gnomad4 EAS AF: 0.000580 AC: 0.000579598 AN: 0.000579598

Gnomad4 SAS AF: 0.0133 AC: 0.0132946 AN: 0.0132946

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00112 AC: 0.00112114 AN: 0.00112114

Gnomad4 OTH AF: 0.00190 AC: 0.00189934 AN: 0.00189934

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
LIST_S2	Benign	0.82	.;T;T;.;T
MetaRNN	Benign	0.0062	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;L;.;L;L
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
Mutation Taster		=92/8	polymorphism

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;