rs2287218

Positions:

chr12-109581533-C-T

Variant summary

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

The NM_000431.4(MVK):c.510C>T(p.Asp170=) 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

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 -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 ClinVar 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 Lovd as [Benign].

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/exons	MANE	UniProt
MVK	NM_000431.4 linkuse as main transcript	c.510C>T	p.Asp170=	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.510C>T	p.Asp170=	synonymous_variant	5/11	1	NM_000431.4	P1

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

GnomAD3 exomes

AF:

0.161

AC:

40401

AN:

251288

Hom.:

3325

AF XY:

0.161

AC XY:

21829

AN XY:

135852

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 SAS exome

AF:

0.142

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

Gnomad4 AFR exome

AF:

0.187

Gnomad4 AMR exome

AF:

0.145

Gnomad4 ASJ exome

AF:

0.190

Gnomad4 EAS exome

AF:

0.160

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.108

Gnomad4 NFE exome

AF:

0.179

Gnomad4 OTH exome

AF:

0.172

GnomAD4 genome

AF:

0.170

AC:

25908

AN:

152194

Hom.:

2294

Cov.:

AF XY:

0.165

AC XY:

12246

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.191

Gnomad4 AMR

AF:

0.157

Gnomad4 ASJ

AF:

0.192

Gnomad4 EAS

AF:

0.140

Gnomad4 SAS

AF:

0.130

Gnomad4 FIN

AF:

0.0985

Gnomad4 NFE

AF:

0.175

Gnomad4 OTH

AF:

0.176

Alfa

AF:

0.178

Hom.:

3170

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

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	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. -
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, 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	Jan 16, 2019	This variant is associated with the following publications: (PMID: 19888504, 15536479, 27190114, 11313769) -
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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mevalonic aciduria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

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

Jan 20, 2022

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Hyperimmunoglobulin D with periodic fever

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.58

DANN

Benign

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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