rs3759387

Positions:

• chr12-109574662-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000431.4(MVK):​c.-14-147G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 708,672 control chromosomes in the GnomAD database, including 28,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (7448 hom., cov: 33)
  • Exomes 𝑓: 0.27 (21509 hom.)
• Consequence: MVK NM_000431.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-109574662-G-T is Benign according to our data. Variant chr12-109574662-G-T is described in ClinVar as [Benign]. Clinvar id is 1287574.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4	c.-14-147G>T		intron_variant		ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8	c.-14-147G>T		intron_variant		1	NM_000431.4	P1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46597 AN: 152026 Hom.: 7421 Cov.: 33

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.316

GnomAD4 exome AF: 0.271 AC: 150650 AN: 556528 Hom.: 21509 AF XY: 0.270 AC XY: 80440 AN XY: 298234

Gnomad4 AFR exome AF: 0.401

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.307 AC: 46672 AN: 152144 Hom.: 7448 Cov.: 33 AF XY: 0.305 AC XY: 22688 AN XY: 74372

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.313

Alfa AF: 0.288 Hom.: 3536

Bravo AF: 0.311

Asia WGS AF: 0.182 AC: 635 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.0
DANN	Benign	0.86

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: rs3759387; hg19: chr12-110012467;