12-109578754-G-A

Position:

• chr12-109578754-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000228510.8(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 ENST00000228510.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752

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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MVK	NM_000431.4	c.227-1048G>A		intron_variant		ENST00000228510.8	NP_000422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8	c.227-1048G>A		intron_variant		1	NM_000431.4	ENSP00000228510	P1

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

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0989

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.174

Alfa AF: 0.172 Hom.: 369

Bravo AF: 0.176

Asia WGS AF: 0.151 AC: 524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.56
DANN	Benign	0.61

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: rs4766613; hg19: chr12-110016559;