rs7957619

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 129638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109576074-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MVK	NM_000431.4 linkuse as main transcript	c.155G>A	p.Ser52Asn	missense_variant	3/11	ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8 linkuse as main transcript	c.155G>A	p.Ser52Asn	missense_variant	3/11	1	NM_000431.4	ENSP00000228510	P1

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

GnomAD3 exomes

AF:

0.101

AC:

25336

AN:

251452

Hom.:

1677

AF XY:

0.101

AC XY:

13757

AN XY:

135906

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 SAS exome

AF:

0.0401

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

Gnomad4 AFR exome

AF:

0.0913

Gnomad4 AMR exome

AF:

0.0763

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0424

Gnomad4 FIN exome

AF:

0.132

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.109

GnomAD4 genome

AF:

0.111

AC:

16852

AN:

152208

Hom.:

1116

Cov.:

AF XY:

0.109

AC XY:

8105

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0892

Gnomad4 AMR

AF:

0.0990

Gnomad4 ASJ

AF:

0.191

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0359

Gnomad4 FIN

AF:

0.137

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.125

Alfa

AF:

0.126

Hom.:

3324

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, 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: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32238606) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mevalonic aciduria

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Methylmalonic acidemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hyperimmunoglobulin D with periodic fever

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

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

MutationTaster

Benign

1.0

P;P;P;P;P

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

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