NM_000431.4:c.227-1714A>G

Variant names:

• chr12-109578088-A-G
• rs7954144
• NM_000431.4:c.227-1714A>G

Variant summary

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

The NM_000431.4(MVK):​c.227-1714A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 151,830 control chromosomes in the GnomAD database, including 25,717 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 0.57 (25717 hom., cov: 30)
• Consequence: MVK NM_000431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.453
• Publications: 12 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4	c.227-1714A>G		intron_variant	Intron 3 of 10	ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.227-1714A>G		intron_variant	Intron 3 of 10	1	NM_000431.4	ENSP00000228510.3

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86373 AN: 151712 Hom.: 25674 Cov.: 30

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.581

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

GnomAD4 genome AF: 0.570 AC: 86476 AN: 151830 Hom.: 25717 Cov.: 30 AF XY: 0.560 AC XY: 41526 AN XY: 74208

African (AFR) AF: 0.733 AC: 30340 AN: 41386

American (AMR) AF: 0.504 AC: 7688 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1844 AN: 3470

East Asian (EAS) AF: 0.297 AC: 1529 AN: 5150

South Asian (SAS) AF: 0.389 AC: 1873 AN: 4810

European-Finnish (FIN) AF: 0.463 AC: 4878 AN: 10538

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.536 AC: 36403 AN: 67916

Other (OTH) AF: 0.582 AC: 1224 AN: 2104

Alfa AF: 0.514 Hom.: 2082

Bravo AF: 0.584

Asia WGS AF: 0.385 AC: 1339 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.43
PhyloP100		-0.45
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: rs7954144; hg19: chr12-110015893;