Genetic Variant PMVK:p.Arg110Gln (chr1-154926467-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PP3_ModeratePP5BS2_Supporting

The NM_006556.4(PMVK):c.329G>A(p.Arg110Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000322 in 1,613,530 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

PMVK
NM_006556.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.32

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a mutagenesis_site Approximately 20000-fold decrease in Vmax for MgATP. (size 0) in uniprot entity PMVK_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

PP5

Variant 1-154926467-C-T is Pathogenic according to our data. Variant chr1-154926467-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1344669.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 28 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PMVK	NM_006556.4 link	c.329G>A	p.Arg110Gln	missense_variant	Exon 4 of 5	ENST00000368467.4	NP_006547.1
PMVK	NM_001323011.3 link	c.287G>A	p.Arg96Gln	missense_variant	Exon 4 of 5		NP_001309940.1
PMVK	NM_001323012.3 link	c.104G>A	p.Arg35Gln	missense_variant	Exon 4 of 5		NP_001309941.1
PMVK	NM_001348696.2 link	c.104G>A	p.Arg35Gln	missense_variant	Exon 4 of 5		NP_001335625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMVK	ENST00000368467.4 link	c.329G>A	p.Arg110Gln	missense_variant	Exon 4 of 5	1	NM_006556.4	ENSP00000357452.3		Q15126

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000164

AC:

AN:

250600

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000337

AC:

492

AN:

1461338

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

228

AN XY:

726954

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000427

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000184

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000425

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Linear porokeratosis

Pathogenic:1

May 01, 2019

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

-0.21

MutationAssessor

Pathogenic

3.3

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MVP

0.87

MPC

1.4

ClinPred

0.59

GERP RS

4.5

Varity_R

0.94

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over