NM_024006.6:c.134T>A

Variant names:

• chr16-31094596-A-T
• rs104894540
• NM_024006.6:c.134T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_024006.6(VKORC1):​c.134T>A​(p.Val45Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V45A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VKORC1 NM_024006.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-31094596-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2208.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024006.6. 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.134T>A	p.Val45Glu	missense	Exon 1 of 3	NP_076869.1	Q9BQB6-1
	VKORC1	NM_001311311.2		c.134T>A	p.Val45Glu	missense	Exon 1 of 4	NP_001298240.1
	VKORC1	NM_206824.3		c.134T>A	p.Val45Glu	missense	Exon 1 of 2	NP_996560.1	Q9BQB6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.134T>A	p.Val45Glu	missense	Exon 1 of 3	ENSP00000378426.2	Q9BQB6-1
	ENSG00000255439	ENST00000529564.1	TSL:4	c.134T>A	p.Val45Glu	missense	Exon 1 of 5	ENSP00000431371.1	E9PLN8
	VKORC1	ENST00000319788.11	TSL:1	c.134T>A	p.Val45Glu	missense	Exon 1 of 4	ENSP00000326135.7	Q9BQB6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457396 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724968

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110956

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.66		Gain of solvent accessibility (P = 0.006)
MVP		0.89
MPC		1.4
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.0085	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.90

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: rs104894540; hg19: chr16-31105917;