rs76914224

Variant names:

• chr12-109579813-G-A
• rs76914224
• NM_000431.4:c.238G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000431.4(MVK):​c.238G>A​(p.Val80Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,614,236 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V80V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12 O:1
• Conservation: PhyloP100: -1.31
• Publications: 8 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
• mevalonate kinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003958106).
• BP6: Variant 12-109579813-G-A is Benign according to our data. Variant chr12-109579813-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97578.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00238 (363/152350) while in subpopulation AFR AF = 0.00753 (313/41580). AF 95% confidence interval is 0.00684. There are 5 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	NM_000431.4	MANE Select	c.238G>A	p.Val80Ile	missense	Exon 4 of 11	NP_000422.1	Q03426
	MVK	NM_001414512.1		c.238G>A	p.Val80Ile	missense	Exon 4 of 12	NP_001401441.1
	MVK	NM_001114185.3		c.238G>A	p.Val80Ile	missense	Exon 4 of 11	NP_001107657.1	B2RDU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	ENST00000228510.8	TSL:1 MANE Select	c.238G>A	p.Val80Ile	missense	Exon 4 of 11	ENSP00000228510.3	Q03426
	MVK	ENST00000546277.6	TSL:5	c.238G>A	p.Val80Ile	missense	Exon 4 of 11	ENSP00000438153.2	Q03426
	MVK	ENST00000878306.1		c.238G>A	p.Val80Ile	missense	Exon 4 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152232 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00745

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000732 AC: 184 AN: 251456 AF XY: 0.000552

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000334 AC: 488 AN: 1461886 Hom.: 2 Cov.: 31 AF XY: 0.000281 AC XY: 204 AN XY: 727244

African (AFR) AF: 0.00845 AC: 283 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000872 AC: 97 AN: 1112012

Other (OTH) AF: 0.000811 AC: 49 AN: 60392

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152350 Hom.: 5 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74496

African (AFR) AF: 0.00753 AC: 313 AN: 41580

American (AMR) AF: 0.00268 AC: 41 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00120 Hom.: 2

Bravo AF: 0.00281

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Hyperimmunoglobulin D with periodic fever (2)
-	-	1	Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (1)
-	-	1	Mevalonic aciduria (1)
-	-	1	MVK-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.065
DANN	Benign	0.56
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.21
Sift	Benign	0.33	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.074
MVP		0.54
MPC		0.29
ClinPred		0.012	T
GERP RS		-9.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.13
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs76914224; hg19: chr12-110017618;