Genetic Variant LOC124903680:p.Gly58Asp (chr16-31095206-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The XM_047435012.1(LOC124903680):c.173G>A(p.Gly58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000794 in 1,210,968 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 3 hom. )

Consequence

LOC124903680
XM_047435012.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.529

Publications

2 publications found

Variant links:

Genes affected

LOC124903680 (HGNC:):

LOC124903680 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903680	XM_047435012.1 link	c.173G>A	p.Gly58Asp	missense_variant	Exon 1 of 1		XP_047290968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000255439	ENST00000529564.1 link	c.-477G>A		upstream_gene_variant		4		ENSP00000431371.1		E9PLN8

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.000342

AC:

362

AN:

1058778

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

151

AN XY:

519100

show subpopulations

African (AFR)

AF:

0.0120

AC:

284

AN:

23640

American (AMR)

AF:

0.00103

AC:

AN:

17554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16424

East Asian (EAS)

AF:

0.00

AC:

AN:

30098

South Asian (SAS)

AF:

0.0000887

AC:

AN:

56388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26610

Middle Eastern (MID)

AF:

0.000651

AC:

AN:

3070

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

840576

Other (OTH)

AF:

0.00113

AC:

AN:

44418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00394

AC:

600

AN:

152190

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

284

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0135

AC:

562

AN:

41516

American (AMR)

AF:

0.00196

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.00476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

4.2

(source)

DANN

Benign

0.67

PhyloP100

0.53

PromoterAI

-0.038

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over