rs35191208

Positions:

• chr12-109591203-C-T

Variant summary

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

The NM_000431.4(MVK):​c.769-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,595,588 control chromosomes in the GnomAD database, including 23,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2123 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21830 hom.)
• Consequence: MVK NM_000431.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.464

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=-0.8).
• BP6: Variant 12-109591203-C-T is Benign according to our data. Variant chr12-109591203-C-T is described in ClinVar as [Benign]. Clinvar id is 439922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109591203-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MVK	NM_000431.4	c.769-38C>T		intron_variant		ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.769-38C>T		intron_variant		1	NM_000431.4	ENSP00000228510	P1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24946 AN: 152136 Hom.: 2127 Cov.: 33

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.159 AC: 39983 AN: 250774 Hom.: 3270 AF XY: 0.160 AC XY: 21682 AN XY: 135582

Gnomad AFR exome AF: 0.169

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: 0.177

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.172 AC: 248041 AN: 1443334 Hom.: 21830 Cov.: 29 AF XY: 0.170 AC XY: 122485 AN XY: 719038

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.164 AC: 24954 AN: 152254 Hom.: 2123 Cov.: 33 AF XY: 0.158 AC XY: 11788 AN XY: 74440

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0987

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.174

Alfa AF: 0.175 Hom.: 436

Bravo AF: 0.170

Asia WGS AF: 0.150 AC: 520 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22246419, 27884173, 27190114) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

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

Dec 07, 2023

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs35191208; hg19: chr12-110029008; COSMIC: COSV57331954; COSMIC: COSV57331954;