rs104895382

Variant names:

Variant summary

Our verdict is . The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000431.4(MVK):c.346T>C(p.Tyr116His) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MVK
NM_000431.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.95

Publications

7 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: G2P, Orphanet
mevalonate kinase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mevalonic aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet
disseminated superficial actinic porokeratosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
porokeratosis of Mibelli
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MVK links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000431.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

REVEL computational evidence supports a deleterious effect, 0.883

PP5

Variant 12-109579921-T-C is Pathogenic according to our data. Variant chr12-109579921-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 97581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	UniProt
MVK	NM_000431.4	MANE Select	c.346T>C	p.Tyr116His	missense	Exon 4 of 11	NP_000422.1	Q03426
MVK	NM_001414512.1		c.346T>C	p.Tyr116His	missense	Exon 4 of 12	NP_001401441.1
MVK	NM_001114185.3		c.346T>C	p.Tyr116His	missense	Exon 4 of 11	NP_001107657.1	B2RDU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MVK	ENST00000228510.8	TSL:1 MANE Select	c.346T>C	p.Tyr116His	missense	Exon 4 of 11	ENSP00000228510.3	Q03426
MVK	ENST00000546277.6	TSL:5	c.346T>C	p.Tyr116His	missense	Exon 4 of 11	ENSP00000438153.2	Q03426
MVK	ENST00000878306.1		c.346T>C	p.Tyr116His	missense	Exon 4 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251474

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41466

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000686

Hom.:

Bravo

AF:

0.000117

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperimmunoglobulin D with periodic fever (3)

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (2)

MVK-related disorder (1)

not provided (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.7

PhyloP100

5.9

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.88

Sift

Uncertain

0.022

Sift4G

Uncertain

0.0050

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.74

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over