chr12-109576074-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000431.4(MVK):c.155G>A(p.Ser52Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,614,064 control chromosomes in the GnomAD database, including 11,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S52I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1116 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10037 hom. )

Consequence

MVK
NM_000431.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.197

Publications

60 publications found

Variant links:

Genes affected

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MVK Gene-Disease associations (from GenCC):

porokeratosis 3, disseminated superficial actinic type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
hyperimmunoglobulinemia D with periodic fever
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
mevalonic aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
disseminated superficial actinic porokeratosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
porokeratosis of Mibelli
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MVK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027855933).

BP6

Variant 12-109576074-G-A is Benign according to our data. Variant chr12-109576074-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 3 of 11	ENST00000228510.8	NP_000422.1	Q03426B2RDU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 3 of 11	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16839

AN:

152090

Hom.:

1115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0891

Gnomad AMI

AF:

0.201

Gnomad AMR

AF:

0.0992

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0356

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.126

GnomAD2 exomes

AF:

0.101

AC:

25336

AN:

251452

AF XY:

0.101

show subpopulations

Gnomad AFR exome

AF:

0.0908

Gnomad AMR exome

AF:

0.0709

Gnomad ASJ exome

AF:

0.189

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.120

GnomAD4 exome

AF:

0.111

AC:

161702

AN:

1461856

Hom.:

10037

Cov.:

AF XY:

0.110

AC XY:

80146

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0913

AC:

3057

AN:

33480

American (AMR)

AF:

0.0763

AC:

3412

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4697

AN:

26136

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0424

AC:

3656

AN:

86254

European-Finnish (FIN)

AF:

0.132

AC:

7060

AN:

53414

Middle Eastern (MID)

AF:

0.127

AC:

733

AN:

5768

European-Non Finnish (NFE)

AF:

0.119

AC:

132473

AN:

1111986

Other (OTH)

AF:

0.109

AC:

6604

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

8310

16620

24931

33241

41551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4450

8900

13350

17800

22250

<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:

0.111

AC:

16852

AN:

152208

Hom.:

1116

Cov.:

AF XY:

0.109

AC XY:

8105

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0892

AC:

3706

AN:

41540

American (AMR)

AF:

0.0990

AC:

1514

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

662

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.0359

AC:

173

AN:

4824

European-Finnish (FIN)

AF:

0.137

AC:

1450

AN:

10594

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.130

AC:

8857

AN:

67996

Other (OTH)

AF:

0.125

AC:

264

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

768

1535

2303

3070

3838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.123

Hom.:

4456

Bravo

AF:

0.106

TwinsUK

AF:

0.109

AC:

403

ALSPAC

AF:

0.108

AC:

418

ESP6500AA

AF:

0.0890

AC:

392

ESP6500EA

AF:

0.130

AC:

1119

ExAC

AF:

0.102

AC:

12344

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.137

EpiControl

AF:

0.134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3Other:1

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32238606) -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mevalonic aciduria

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylmalonic acidemia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperimmunoglobulin D with periodic fever

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.044

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.0019

.;T;T;T;.;.;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.44

T;T;.;.;T;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.85

.;.;N;.;.;.;.;N

PhyloP100

0.20

PrimateAI

Benign

0.31

PROVEAN

Benign

1.1

N;N;N;N;.;.;.;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;T;T;.;.;.;T

Sift4G

Benign

0.79

T;T;T;T;.;T;T;T

Polyphen

0.0, 0.0020

.;.;B;B;.;.;B;B

Vest4

0.025, 0.052, 0.061, 0.020

MPC

0.33

ClinPred

0.00030

GERP RS

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.035

gMVP

0.31

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over