chr1-154925142-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBS2_Supporting

The NM_006556.4(PMVK):​c.566G>A​(p.Arg189His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,611,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R189C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

PMVK
NM_006556.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.73
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.028216153).
BP6
Variant 1-154925142-C-T is Benign according to our data. Variant chr1-154925142-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3421546.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 7 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 UniProt
PMVKNM_006556.4 linkc.566G>A p.Arg189His missense_variant Exon 5 of 5 ENST00000368467.4 NP_006547.1
PMVKNM_001323011.3 linkc.524G>A p.Arg175His missense_variant Exon 5 of 5 NP_001309940.1
PMVKNM_001323012.3 linkc.341G>A p.Arg114His missense_variant Exon 5 of 5 NP_001309941.1
PMVKNM_001348696.2 linkc.341G>A p.Arg114His missense_variant Exon 5 of 5 NP_001335625.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMVKENST00000368467.4 linkc.566G>A p.Arg189His missense_variant Exon 5 of 5 1 NM_006556.4 ENSP00000357452.3 Q15126

Frequencies

GnomAD3 genomes
AF:
0.0000465
AC:
7
AN:
150486
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000245
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000134
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:
0.0000295
Gnomad OTH
AF:
0.000968
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251428
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461484
Hom.:
0
Cov.:
35
AF XY:
0.0000220
AC XY:
16
AN XY:
727056
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000465
AC:
7
AN:
150486
Hom.:
0
Cov.:
31
AF XY:
0.0000409
AC XY:
3
AN XY:
73288
show subpopulations
Gnomad4 AFR
AF:
0.0000245
Gnomad4 AMR
AF:
0.000134
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.000968
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Benign:1
Oct 23, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
0.096
DANN
Benign
0.58
DEOGEN2
Benign
0.15
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.0055
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.028
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.27
N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
0.020
N
REVEL
Benign
0.023
Sift
Benign
0.55
T
Sift4G
Benign
0.36
T
Polyphen
0.0
B
Vest4
0.043
MVP
0.15
MPC
0.52
ClinPred
0.0094
T
GERP RS
-6.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.040
gMVP
0.22

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: rs375698500; hg19: chr1-154897618; COSMIC: COSV63785724; API