16-31093188-C-T

Variant names:

• chr16-31093188-C-T
• rs8050894
• NM_024006.6:c.283+124G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_024006.6(VKORC1):​c.283+124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,026,858 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.576
• Publications: 115 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-31093188-C-T is Benign according to our data. Variant chr16-31093188-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1316884.Status of the report is criteria_provided_single_submitter, 1 stars.

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.283+124G>A		intron	N/A	NP_076869.1	Q9BQB6-1
	VKORC1	NM_001311311.2		c.283+124G>A		intron	N/A	NP_001298240.1
	VKORC1	NM_206824.3		c.173+1369G>A		intron	N/A	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.283+124G>A		intron	N/A	ENSP00000378426.2	Q9BQB6-1
	ENSG00000255439	ENST00000529564.1	TSL:4	c.283+124G>A		intron	N/A	ENSP00000431371.1	E9PLN8
	VKORC1	ENST00000319788.11	TSL:1	c.283+124G>A		intron	N/A	ENSP00000326135.7	Q9BQB6-2

Frequencies

GnomAD3 genomes AF: 0.000331 AC: 49 AN: 148206 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.00493

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000403 AC: 354 AN: 878652 Hom.: 0 AF XY: 0.000420 AC XY: 188 AN XY: 447668

African (AFR) AF: 0.000220 AC: 5 AN: 22738

American (AMR) AF: 0.00 AC: 0 AN: 34222

Ashkenazi Jewish (ASJ) AF: 0.00523 AC: 105 AN: 20064

East Asian (EAS) AF: 0.00 AC: 0 AN: 34044

South Asian (SAS) AF: 0.0000617 AC: 4 AN: 64806

European-Finnish (FIN) AF: 0.000332 AC: 11 AN: 33086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2982

European-Non Finnish (NFE) AF: 0.000308 AC: 193 AN: 625688

Other (OTH) AF: 0.000878 AC: 36 AN: 41022

GnomAD4 genome AF: 0.000331 AC: 49 AN: 148206 Hom.: 0 Cov.: 28 AF XY: 0.000277 AC XY: 20 AN XY: 72084

African (AFR) AF: 0.000125 AC: 5 AN: 40012

American (AMR) AF: 0.000137 AC: 2 AN: 14638

Ashkenazi Jewish (ASJ) AF: 0.00493 AC: 17 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4550

European-Finnish (FIN) AF: 0.000102 AC: 1 AN: 9826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.000356 AC: 24 AN: 67332

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.0000125 Hom.: 6711

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.58
PromoterAI		-0.015	Neutral

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: rs8050894; hg19: chr16-31104509;