rs34368092

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.405G>A(p.Ser135Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.048 in 1,614,080 control chromosomes in the GnomAD database, including 2,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 285 hom., cov: 33)

Exomes 𝑓: 0.048 ( 2152 hom. )

Consequence

MVK
NM_000431.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -4.38

Publications

14 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=-0.92).

BP6

Variant 12-109581428-G-A is Benign according to our data. Variant chr12-109581428-G-A is described in ClinVar as Benign. ClinVar VariationId is 129639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4 link	c.405G>A	p.Ser135Ser	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.405G>A	p.Ser135Ser	synonymous_variant	Exon 5 of 11	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.0512

AC:

7787

AN:

152146

Hom.:

285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0394

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0306

Gnomad ASJ

AF:

0.0694

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.0916

Gnomad MID

AF:

0.0701

Gnomad NFE

AF:

0.0623

Gnomad OTH

AF:

0.0503

GnomAD2 exomes

AF:

0.0449

AC:

11281

AN:

251052

AF XY:

0.0448

show subpopulations

Gnomad AFR exome

AF:

0.0403

Gnomad AMR exome

AF:

0.0240

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0861

Gnomad NFE exome

AF:

0.0584

Gnomad OTH exome

AF:

0.0505

GnomAD4 exome

AF:

0.0477

AC:

69725

AN:

1461814

Hom.:

2152

Cov.:

AF XY:

0.0477

AC XY:

34668

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0416

AC:

1394

AN:

33476

American (AMR)

AF:

0.0259

AC:

1160

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0636

AC:

1661

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0133

AC:

1151

AN:

86254

European-Finnish (FIN)

AF:

0.0876

AC:

4675

AN:

53394

Middle Eastern (MID)

AF:

0.0582

AC:

334

AN:

5742

European-Non Finnish (NFE)

AF:

0.0509

AC:

56571

AN:

1112002

Other (OTH)

AF:

0.0460

AC:

2775

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4489

8979

13468

17958

22447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1850

3700

5550

7400

9250

<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:

0.0512

AC:

7795

AN:

152266

Hom.:

285

Cov.:

AF XY:

0.0507

AC XY:

3776

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0395

AC:

1640

AN:

41570

American (AMR)

AF:

0.0306

AC:

468

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0694

AC:

241

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0112

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0916

AC:

972

AN:

10614

Middle Eastern (MID)

AF:

0.0822

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0623

AC:

4234

AN:

67998

Other (OTH)

AF:

0.0497

AC:

105

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

385

770

1156

1541

1926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0585

Hom.:

211

Bravo

AF:

0.0446

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0588

EpiControl

AF:

0.0528

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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: MAF -

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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. -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mevalonic aciduria

Benign:1

Jan 13, 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

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperimmunoglobulin D with periodic fever

Benign:1

Jan 13, 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

-0.92

CADD

Benign

0.27

(source)

DANN

Benign

0.64

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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