12-109581533-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000431.4(MVK):c.510C>T(p.Asp170Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,614,050 control chromosomes in the GnomAD database, including 24,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2294 hom., cov: 33)

Exomes 𝑓: 0.17 ( 22185 hom. )

Consequence

MVK
NM_000431.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.43

Publications

39 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 12-109581533-C-T is Benign according to our data. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581533-C-T is described in CliVar as Benign. Clinvar id is 129640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4 link	c.510C>T	p.Asp170Asp	synonymous_variant	Exon 5 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.510C>T	p.Asp170Asp	synonymous_variant	Exon 5 of 11	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25901

AN:

152076

Hom.:

2298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.216

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.0985

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.173

GnomAD2 exomes

AF:

0.161

AC:

40401

AN:

251288

AF XY:

0.161

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.172

AC:

252078

AN:

1461856

Hom.:

22185

Cov.:

AF XY:

0.171

AC XY:

124209

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.187

AC:

6264

AN:

33480

American (AMR)

AF:

0.145

AC:

6496

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

4973

AN:

26136

East Asian (EAS)

AF:

0.160

AC:

6344

AN:

39700

South Asian (SAS)

AF:

0.139

AC:

11948

AN:

86258

European-Finnish (FIN)

AF:

0.108

AC:

5745

AN:

53418

Middle Eastern (MID)

AF:

0.203

AC:

1170

AN:

5768

European-Non Finnish (NFE)

AF:

0.179

AC:

198736

AN:

1111980

Other (OTH)

AF:

0.172

AC:

10402

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

14070

28140

42209

56279

70349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7026

14052

21078

28104

35130

<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:

0.170

AC:

25908

AN:

152194

Hom.:

2294

Cov.:

AF XY:

0.165

AC XY:

12246

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.191

AC:

7927

AN:

41528

American (AMR)

AF:

0.157

AC:

2401

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

664

AN:

3466

East Asian (EAS)

AF:

0.140

AC:

722

AN:

5160

South Asian (SAS)

AF:

0.130

AC:

629

AN:

4832

European-Finnish (FIN)

AF:

0.0985

AC:

1045

AN:

10608

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.175

AC:

11900

AN:

67990

Other (OTH)

AF:

0.176

AC:

371

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1120

2239

3359

4478

5598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.178

Hom.:

3943

Bravo

AF:

0.177

Asia WGS

AF:

0.151

AC:

524

AN:

3478

EpiCase

AF:

0.182

EpiControl

AF:

0.181

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

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. -

not provided

Benign:3Other:1

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Jan 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19888504, 15536479, 27190114, 11313769) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mevalonic aciduria

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Jan 20, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hyperimmunoglobulin D with periodic fever

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.58

(source)

DANN

Benign

0.49

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism (auto)

(source)

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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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