rs3759387

Variant names:

• chr12-109574662-G-T
• rs3759387
• NM_000431.4:c.-14-147G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• porokeratosis 3, disseminated superficial actinic type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hyperimmunoglobulinemia D with periodic fever

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• porokeratosis of Mibelli

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1287574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MVK	NM_000431.4	c.-14-147G>T		intron_variant	Intron 1 of 10	ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.-14-147G>T		intron_variant	Intron 1 of 10	1	NM_000431.4	ENSP00000228510.3

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

African (AFR) AF: 0.401 AC: 6200 AN: 15474

American (AMR) AF: 0.284 AC: 9454 AN: 33318

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 5416 AN: 18620

East Asian (EAS) AF: 0.119 AC: 3686 AN: 31040

South Asian (SAS) AF: 0.234 AC: 14133 AN: 60344

European-Finnish (FIN) AF: 0.296 AC: 10549 AN: 35614

Middle Eastern (MID) AF: 0.305 AC: 723 AN: 2370

European-Non Finnish (NFE) AF: 0.280 AC: 92252 AN: 329884

Other (OTH) AF: 0.276 AC: 8237 AN: 29864

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

African (AFR) AF: 0.395 AC: 16398 AN: 41478

American (AMR) AF: 0.295 AC: 4504 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 977 AN: 3468

East Asian (EAS) AF: 0.133 AC: 691 AN: 5188

South Asian (SAS) AF: 0.218 AC: 1051 AN: 4830

European-Finnish (FIN) AF: 0.298 AC: 3158 AN: 10592

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18917 AN: 67990

Other (OTH) AF: 0.313 AC: 658 AN: 2104

Alfa AF: 0.291 Hom.: 4910

Bravo AF: 0.311

Asia WGS AF: 0.182 AC: 635 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.0
DANN	Benign	0.86
PhyloP100		1.1
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3759387; hg19: chr12-110012467;