12-109578754-G-A

Variant names:

• chr12-109578754-G-A
• rs4766613
• NM_000431.4:c.227-1048G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000431.4(MVK):​c.227-1048G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,152 control chromosomes in the GnomAD database, including 2,245 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2245 hom., cov: 33)
• Consequence: MVK NM_000431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	NM_000431.4	MANE Select	c.227-1048G>A		intron	N/A	NP_000422.1
	MVK	NM_001414512.1		c.227-1048G>A		intron	N/A	NP_001401441.1
	MVK	NM_001114185.3		c.227-1048G>A		intron	N/A	NP_001107657.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	ENST00000228510.8	TSL:1 MANE Select	c.227-1048G>A		intron	N/A	ENSP00000228510.3
	MVK	ENST00000546277.6	TSL:5	c.227-1048G>A		intron	N/A	ENSP00000438153.2
	MVK	ENST00000636996.1	TSL:5	c.218+2609G>A		intron	N/A	ENSP00000490869.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25704 AN: 152034 Hom.: 2249 Cov.: 33

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0989

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.171

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.169 AC: 25711 AN: 152152 Hom.: 2245 Cov.: 33 AF XY: 0.163 AC XY: 12162 AN XY: 74410

African (AFR) AF: 0.187 AC: 7745 AN: 41498

American (AMR) AF: 0.157 AC: 2394 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3468

East Asian (EAS) AF: 0.140 AC: 723 AN: 5176

South Asian (SAS) AF: 0.130 AC: 627 AN: 4822

European-Finnish (FIN) AF: 0.0989 AC: 1047 AN: 10584

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11898 AN: 68004

Other (OTH) AF: 0.174 AC: 367 AN: 2108

Alfa AF: 0.172 Hom.: 378

Bravo AF: 0.176

Asia WGS AF: 0.151 AC: 524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.56
DANN	Benign	0.61
PhyloP100		-0.75
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: rs4766613; hg19: chr12-110016559;