ENST00000319788.11:c.440C>T

Variant names:

• chr16-31091268-G-A
• rs7200749
• ENST00000319788.11:c.440C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000319788.11(VKORC1):​c.440C>T​(p.Pro147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,136 control chromosomes in the GnomAD database, including 1,541 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (759 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (782 hom.)
• Consequence: VKORC1 ENST00000319788.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15
• Publications: 25 publications found

Genes affected

VKORC1 (HGNC:23663): (vitamin K epoxide reductase complex subunit 1) This gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for the reduction of inactive vitamin K 2,3-epoxide to active vitamin K in the endoplasmic reticulum membrane. Vitamin K is a required co-factor for carboxylation of glutamic acid residues by vitamin K-dependent gamma-carboxylase in blood-clotting enzymes. Allelic variation in this gene is associated with vitamin k-dependent clotting factors combined deficiency of 2, and increased resistance or sensitivity to warfarin, an inhibitor of vitamin K epoxide reductase. Pseudogenes of this gene are located on chromosomes 1 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

VKORC1 Gene-Disease associations (from GenCC):

• vitamin K-dependent clotting factors, combined deficiency of, type 2

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255439 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016042292).
• BP6: Variant 16-31091268-G-A is Benign according to our data. Variant chr16-31091268-G-A is described in ClinVar as Benign. ClinVar VariationId is 318975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000319788.11. 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
	VKORC1	NM_024006.6	MANE Select	c.358C>T	p.Leu120Leu	synonymous	Exon 3 of 3	NP_076869.1	Q9BQB6-1
	VKORC1	NM_206824.3		c.248C>T	p.Pro83Leu	missense	Exon 2 of 2	NP_996560.1	Q9BQB6-3
	VKORC1	NM_001311311.2		c.442C>T	p.Leu148Leu	synonymous	Exon 4 of 4	NP_001298240.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000319788.11	TSL:1	c.440C>T	p.Pro147Leu	missense	Exon 4 of 4	ENSP00000326135.7	Q9BQB6-2
	VKORC1	ENST00000354895.4	TSL:1	c.248C>T	p.Pro83Leu	missense	Exon 2 of 2	ENSP00000346969.4	Q9BQB6-3
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.358C>T	p.Leu120Leu	synonymous	Exon 3 of 3	ENSP00000378426.2	Q9BQB6-1

Frequencies

GnomAD3 genomes AF: 0.0553 AC: 8410 AN: 152170 Hom.: 751 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.0382

GnomAD2 exomes AF: 0.0156 AC: 3912 AN: 251144 AF XY: 0.0119

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00685 AC: 10020 AN: 1461848 Hom.: 782 Cov.: 32 AF XY: 0.00615 AC XY: 4474 AN XY: 727222

African (AFR) AF: 0.206 AC: 6882 AN: 33480

American (AMR) AF: 0.0131 AC: 588 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00612 AC: 160 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5768

European-Non Finnish (NFE) AF: 0.00117 AC: 1299 AN: 1112012

Other (OTH) AF: 0.0148 AC: 894 AN: 60394

GnomAD4 genome AF: 0.0554 AC: 8441 AN: 152288 Hom.: 759 Cov.: 32 AF XY: 0.0540 AC XY: 4023 AN XY: 74458

African (AFR) AF: 0.188 AC: 7822 AN: 41542

American (AMR) AF: 0.0261 AC: 400 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68030

Other (OTH) AF: 0.0378 AC: 80 AN: 2116

Alfa AF: 0.0182 Hom.: 369

Bravo AF: 0.0628

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.188 AC: 825

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0190 AC: 2303

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00249

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Vitamin K-dependent clotting factors, combined deficiency of, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	9.0
DANN	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.92	T
PhyloP100		2.2
PROVEAN	Benign	1.8	N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0040	B
Vest4		0.21
ClinPred		0.039	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=94/6	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: rs7200749; hg19: chr16-31102589; COSMIC: COSV54925112; COSMIC: COSV54925112;