chr12-109581533-C-T

Variant names:

• chr12-109581533-C-T
• rs2287218
• NM_000431.4:c.510C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001414515.1(MVK):​c.-73C>T variant causes a 5 prime UTR premature start codon gain 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_001414515.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -4.43

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]

ACMG classification

Verdict is Benign. Variant got -20 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].
• 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 rank	MANE	Protein	UniProt
MVK	NM_000431.4	c.510C>T	p.Asp170Asp	synonymous_variant	Exon 5 of 11	ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.510C>T	p.Asp170Asp	synonymous_variant	Exon 5 of 11	1	NM_000431.4	ENSP00000228510.3

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25901 AN: 152076 Hom.: 2298 Cov.: 33

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

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.: 35 AF XY: 0.171 AC XY: 124209 AN XY: 727232

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.: 33 AF XY: 0.165 AC XY: 12246 AN XY: 74412

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:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. 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

- -

-

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3 Other: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. -

Jan 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19888504, 15536479, 27190114, 11313769) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 19, 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 12, 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

Jan 20, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hyperimmunoglobulin D with periodic fever Benign:1

Jan 12, 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. -

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

Other links and lift over

dbSNP: rs2287218; hg19: chr12-110019338; COSMIC: COSV57331947; COSMIC: COSV57331947;