Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_000431.4(MVK):c.764T>C(p.Leu255Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

MVK
NM_000431.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.49

Publications

3 publications found

Variant links:

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

MVK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-109590857-T-C is Pathogenic according to our data. Variant chr12-109590857-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 39724.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MVK	NM_000431.4	MANE Select	c.764T>C	p.Leu255Pro	missense	Exon 8 of 11	NP_000422.1
MVK	NM_001414512.1		c.839T>C	p.Leu280Pro	missense	Exon 9 of 12	NP_001401441.1
MVK	NM_001114185.3		c.764T>C	p.Leu255Pro	missense	Exon 8 of 11	NP_001107657.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MVK	ENST00000228510.8	TSL:1 MANE Select	c.764T>C	p.Leu255Pro	missense	Exon 8 of 11	ENSP00000228510.3
MVK	ENST00000546277.6	TSL:5	c.764T>C	p.Leu255Pro	missense	Exon 8 of 11	ENSP00000438153.2
MVK	ENST00000636996.1	TSL:5	c.611T>C	p.Leu204Pro	missense	Exon 6 of 9	ENSP00000490869.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000131

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Porokeratosis 3, disseminated superficial actinic type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Benign

0.035

Eigen_PC

Benign

0.0063

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.8

PhyloP100

2.5

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.74

Sift

Benign

0.30

Sift4G

Benign

0.34

Polyphen

0.88

Vest4

0.85

MutPred

0.49

Loss of stability (P = 0.0198)

MVP

0.98

MPC

0.85

ClinPred

0.67

GERP RS

1.8

Varity_R

0.66

gMVP

0.91

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over