rs66486014

Positions:

• chr12-109573660-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000546277.6(MVK):​c.-15+89G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 757,782 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (36 hom.)
• Consequence: MVK ENST00000546277.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.87

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-109573660-G-A is Benign according to our data. Variant chr12-109573660-G-A is described in ClinVar as [Benign]. Clinvar id is 534562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00701 (1068/152360) while in subpopulation NFE AF= 0.0103 (704/68028). AF 95% confidence interval is 0.00971. There are 6 homozygotes in gnomad4. There are 512 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	XM_017019313.3	c.-15+89G>A		intron_variant
MVK	XM_047428873.1	c.286+89G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000539335.5	c.-6+89G>A		intron_variant		3
MVK	ENST00000546277.6	c.-15+89G>A		intron_variant		5		P1
MVK	ENST00000535044.1	n.231+89G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1068 AN: 152242 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00887 AC: 5370 AN: 605422 Hom.: 36 Cov.: 7 AF XY: 0.00841 AC XY: 2684 AN XY: 319150

Gnomad4 AFR exome AF: 0.00202

Gnomad4 AMR exome AF: 0.00482

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0000313

Gnomad4 SAS exome AF: 0.00166

Gnomad4 FIN exome AF: 0.00841

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.00942

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152360 Hom.: 6 Cov.: 33 AF XY: 0.00687 AC XY: 512 AN XY: 74504

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00753

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00603 Hom.: 2

Bravo AF: 0.00663

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2023

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 19, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

MMAB: BS1, BS2; MVK: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.92

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: rs66486014; hg19: chr12-110011465;