rs34368092

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000431.4(MVK):c.405G>A(p.Ser135=) 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:11O:1

Conservation

PhyloP100: -4.38

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 129639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109581428-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
MVK	NM_000431.4 linkuse as main transcript	c.405G>A	p.Ser135=	synonymous_variant	5/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8 linkuse as main transcript	c.405G>A	p.Ser135=	synonymous_variant	5/11	1	NM_000431.4	P1

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

GnomAD3 exomes

AF:

0.0449

AC:

11281

AN:

251052

Hom.:

375

AF XY:

0.0448

AC XY:

6080

AN XY:

135744

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 SAS exome

AF:

0.0116

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

Gnomad4 AFR exome

AF:

0.0416

Gnomad4 AMR exome

AF:

0.0259

Gnomad4 ASJ exome

AF:

0.0636

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0133

Gnomad4 FIN exome

AF:

0.0876

Gnomad4 NFE exome

AF:

0.0509

Gnomad4 OTH exome

AF:

0.0460

GnomAD4 genome

AF:

0.0512

AC:

7795

AN:

152266

Hom.:

285

Cov.:

AF XY:

0.0507

AC XY:

3776

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0395

Gnomad4 AMR

AF:

0.0306

Gnomad4 ASJ

AF:

0.0694

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.0916

Gnomad4 NFE

AF:

0.0623

Gnomad4 OTH

AF:

0.0497

Alfa

AF:

0.0587

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:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

Mevalonic aciduria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Hyperimmunoglobulin D with periodic fever

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

Cadd

Benign

0.27

Dann

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over