16-31090989-A-G

Variant names:

• chr16-31090989-A-G
• rs886051933
• NM_024006.6:c.*145T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024006.6(VKORC1):​c.*145T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000574 in 1,220,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: VKORC1 NM_024006.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).

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.*145T>C		3_prime_UTR	Exon 3 of 3	NP_076869.1	Q9BQB6-1
	VKORC1	NM_001311311.2		c.*145T>C		3_prime_UTR	Exon 4 of 4	NP_001298240.1
	VKORC1	NM_206824.3		c.*248T>C		3_prime_UTR	Exon 2 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.*145T>C		3_prime_UTR	Exon 3 of 3	ENSP00000378426.2	Q9BQB6-1
	VKORC1	ENST00000319788.11	TSL:1	c.*248T>C		3_prime_UTR	Exon 4 of 4	ENSP00000326135.7	Q9BQB6-2
	VKORC1	ENST00000354895.4	TSL:1	c.*248T>C		3_prime_UTR	Exon 2 of 2	ENSP00000346969.4	Q9BQB6-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000574 AC: 7 AN: 1220362 Hom.: 0 Cov.: 17 AF XY: 0.00000660 AC XY: 4 AN XY: 605758

African (AFR) AF: 0.00 AC: 0 AN: 28016

American (AMR) AF: 0.00 AC: 0 AN: 32600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22194

East Asian (EAS) AF: 0.00 AC: 0 AN: 34754

South Asian (SAS) AF: 0.00 AC: 0 AN: 71940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3670

European-Non Finnish (NFE) AF: 0.00000749 AC: 7 AN: 935024

Other (OTH) AF: 0.00 AC: 0 AN: 51816

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Vitamin K-Dependent Clotting Factors (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.3
DANN	Benign	0.65
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886051933; hg19: chr16-31102310;