chr12-109586736-A-G

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.632-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,612,244 control chromosomes in the GnomAD database, including 52,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5181 hom., cov: 33)

Exomes 𝑓: 0.25 ( 46821 hom. )

Consequence

MVK
NM_000431.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.96

Publications

17 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 (BayesDel_noAF=-0.87).

BP6

Variant 12-109586736-A-G is Benign according to our data. Variant chr12-109586736-A-G is described in ClinVar as Benign. ClinVar VariationId is 138312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4 link	c.632-18A>G		intron_variant	Intron 6 of 10	ENST00000228510.8	NP_000422.1	Q03426B2RDU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8 link	c.632-18A>G		intron_variant	Intron 6 of 10	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38785

AN:

152014

Hom.:

5177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.311

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.250

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.230

AC:

57672

AN:

251140

AF XY:

0.230

show subpopulations

Gnomad AFR exome

AF:

0.310

Gnomad AMR exome

AF:

0.183

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.172

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.261

Gnomad OTH exome

AF:

0.239

GnomAD4 exome

AF:

0.250

AC:

365109

AN:

1460112

Hom.:

46821

Cov.:

AF XY:

0.248

AC XY:

179938

AN XY:

726430

show subpopulations

African (AFR)

AF:

0.305

AC:

10213

AN:

33446

American (AMR)

AF:

0.186

AC:

8324

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

6702

AN:

26120

East Asian (EAS)

AF:

0.182

AC:

7243

AN:

39688

South Asian (SAS)

AF:

0.187

AC:

16136

AN:

86202

European-Finnish (FIN)

AF:

0.173

AC:

9209

AN:

53322

Middle Eastern (MID)

AF:

0.298

AC:

1720

AN:

5768

European-Non Finnish (NFE)

AF:

0.262

AC:

290645

AN:

1110544

Other (OTH)

AF:

0.247

AC:

14917

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

14105

28210

42316

56421

70526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9738

19476

29214

38952

48690

<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:

0.255

AC:

38820

AN:

152132

Hom.:

5181

Cov.:

AF XY:

0.248

AC XY:

18430

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.311

AC:

12891

AN:

41480

American (AMR)

AF:

0.207

AC:

3167

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

867

AN:

3466

East Asian (EAS)

AF:

0.165

AC:

856

AN:

5176

South Asian (SAS)

AF:

0.172

AC:

832

AN:

4826

European-Finnish (FIN)

AF:

0.166

AC:

1756

AN:

10600

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17516

AN:

67980

Other (OTH)

AF:

0.264

AC:

559

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1530

3059

4589

6118

7648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.196

Hom.:

658

Bravo

AF:

0.264

Asia WGS

AF:

0.204

AC:

708

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0010

(source)

DANN

Benign

0.41

PhyloP100

-6.0

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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