rs1350346775

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_006556.4(PMVK):c.436A>T(p.Thr146Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T146M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PMVK
NM_006556.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.47

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: G2P, Labcorp Genetics (formerly Invitae), 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_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21131876).

BP6

Variant 1-154926360-T-A is Benign according to our data. Variant chr1-154926360-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2639382.Status of the report is criteria_provided_single_submitter, 1 stars.

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.436A>T	p.Thr146Ser	missense	Exon 4 of 5	NP_006547.1	Q6FGV9
PMVK	NM_001323011.3		c.394A>T	p.Thr132Ser	missense	Exon 4 of 5	NP_001309940.1
PMVK	NM_001323012.3		c.211A>T	p.Thr71Ser	missense	Exon 4 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.436A>T	p.Thr146Ser	missense	Exon 4 of 5	ENSP00000357452.3	Q15126
PMVK	ENST00000940351.1		c.628A>T	p.Thr210Ser	missense	Exon 5 of 6	ENSP00000610410.1
PMVK	ENST00000885059.1		c.475A>T	p.Thr159Ser	missense	Exon 5 of 6	ENSP00000555118.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000478

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250220

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460758

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111600

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.34

Eigen

Benign

-0.087

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

M_CAP

Benign

0.010

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

3.5

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.14

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.025

Polyphen

0.015

Vest4

0.25

MutPred

0.36

Gain of disorder (P = 0.0548)

MVP

0.38

MPC

0.38

ClinPred

0.79

GERP RS

3.5

Varity_R

0.30

gMVP

0.34

Mutation Taster

=81/19

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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