Genetic Variant NM_024006.6:c.*145T>C (chr16-31090989-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

Publications

0 publications found

Variant links:

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

VKORC1 links:

ENSG00000255439 (HGNC:):

ENSG00000255439 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6 link	c.*145T>C	3_prime_UTR_variant	Exon 3 of 3	ENST00000394975.3	NP_076869.1	Q9BQB6-1A0A0S2Z6I4
VKORC1	NM_001311311.2 link	c.*145T>C	3_prime_UTR_variant	Exon 4 of 4		NP_001298240.1	Q9BQB6
VKORC1	NM_206824.3 link	c.*248T>C	3_prime_UTR_variant	Exon 2 of 2		NP_996560.1	Q9BQB6-3A0A0S2Z5X7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 link	c.*145T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_024006.6	ENSP00000378426.2		Q9BQB6-1
ENSG00000255439	ENST00000529564.1 link	c.283+2323T>C		intron_variant	Intron 2 of 4	4		ENSP00000431371.1		E9PLN8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000574

AC:

AN:

1220362

Hom.:

Cov.:

AF XY:

0.00000660

AC XY:

AN XY:

605758

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28016

American (AMR)

AF:

0.00

AC:

AN:

32600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22194

East Asian (EAS)

AF:

0.00

AC:

AN:

34754

South Asian (SAS)

AF:

0.00

AC:

AN:

71940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3670

European-Non Finnish (NFE)

AF:

0.00000749

AC:

AN:

935024

Other (OTH)

AF:

0.00

AC:

AN:

51816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.604

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vitamin K-Dependent Clotting Factors

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.3

(source)

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

Publications

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NM_024006.6:c.*145T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over