1-154926467-C-T

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).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

PMVK
NM_006556.4 missense

Scores

8
9
2

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]

Genome browser will be placed here

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/exons MANE UniProt
PMVKNM_006556.4 linkuse as main transcriptc.329G>A p.Arg110Gln missense_variant 4/5 ENST00000368467.4
PMVKNM_001323011.3 linkuse as main transcriptc.287G>A p.Arg96Gln missense_variant 4/5
PMVKNM_001323012.3 linkuse as main transcriptc.104G>A p.Arg35Gln missense_variant 4/5
PMVKNM_001348696.2 linkuse as main transcriptc.104G>A p.Arg35Gln missense_variant 4/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMVKENST00000368467.4 linkuse as main transcriptc.329G>A p.Arg110Gln missense_variant 4/51 NM_006556.4 P1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152192
Hom.:
0
Cov.:
32
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:
41
AN:
250600
Hom.:
0
AF XY:
0.000155
AC XY:
21
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.:
0
Cov.:
31
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:
28
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
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.:
0
Bravo
AF:
0.000212
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000140
AC:
17
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
Likely pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityMay 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.71
D
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Pathogenic
3.3
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.9
D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.95
MVP
0.87
MPC
1.4
ClinPred
0.59
D
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.

Other links and lift over

dbSNP: rs140728783; hg19: chr1-154898943; COSMIC: COSV63785609; API