Genetic Variant NM_006556.4:c.509A>G (chr1-154925199-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_006556.4(PMVK):c.509A>G(p.Asn170Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 151,914 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Consequence

PMVK
NM_006556.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.26

Publications

0 publications found

Variant links:

Genes affected

PMVK (HGNC:9141): (phosphomevalonate kinase) This gene encodes a peroxisomal enzyme that is a member of the galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase (GHMP) family of ATP-dependent enzymes. The encoded protein catalyzes the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate, which is the fifth step in the mevalonate pathway of isoprenoid biosynthesis. Mutations in this gene are linked to certain types of porokeratosis including disseminated superficial porokeratosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

PMVK Gene-Disease associations (from GenCC):

porokeratosis 1, Mibelli type
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
porokeratosis of Mibelli
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autoinflammatory syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PMVK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity PMVK_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006556.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMVK	NM_006556.4	MANE Select	c.509A>G	p.Asn170Ser	missense	Exon 5 of 5	NP_006547.1	Q6FGV9
PMVK	NM_001323011.3		c.467A>G	p.Asn156Ser	missense	Exon 5 of 5	NP_001309940.1
PMVK	NM_001323012.3		c.284A>G	p.Asn95Ser	missense	Exon 5 of 5	NP_001309941.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMVK	ENST00000368467.4	TSL:1 MANE Select	c.509A>G	p.Asn170Ser	missense	Exon 5 of 5	ENSP00000357452.3	Q15126
PMVK	ENST00000940351.1		c.701A>G	p.Asn234Ser	missense	Exon 6 of 6	ENSP00000610410.1
PMVK	ENST00000885059.1		c.548A>G	p.Asn183Ser	missense	Exon 6 of 6	ENSP00000555118.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000398

AC:

AN:

251442

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151914

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74188

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41356

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000658

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

-0.25

MutationAssessor

Pathogenic

3.2

PhyloP100

5.3

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.73

MPC

1.1

ClinPred

1.0

GERP RS

5.3

Varity_R

0.84

gMVP

0.90

Mutation Taster

=33/67

disease causing

(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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over