rs7954144

Positions:

• chr12-109578088-A-G
• chr12-109578088-A-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	Protein	UniProt
MVK	NM_000431.4	c.227-1714A>G		intron_variant		ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.227-1714A>G		intron_variant		1	NM_000431.4	ENSP00000228510	P1

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

Gnomad4 AFR AF: 0.733

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.582

Alfa AF: 0.503 Hom.: 1897

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

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: rs7954144; hg19: chr12-110015893;