1-154926405-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_006556.4(PMVK):​c.391G>A​(p.Val131Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V131L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

PMVK
NM_006556.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.00
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.09488514).
BP6
Variant 1-154926405-C-T is Benign according to our data. Variant chr1-154926405-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2351691.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMVKNM_006556.4 linkc.391G>A p.Val131Ile missense_variant Exon 4 of 5 ENST00000368467.4 NP_006547.1
PMVKNM_001323011.3 linkc.349G>A p.Val117Ile missense_variant Exon 4 of 5 NP_001309940.1
PMVKNM_001323012.3 linkc.166G>A p.Val56Ile missense_variant Exon 4 of 5 NP_001309941.1
PMVKNM_001348696.2 linkc.166G>A p.Val56Ile missense_variant Exon 4 of 5 NP_001335625.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMVKENST00000368467.4 linkc.391G>A p.Val131Ile missense_variant Exon 4 of 5 1 NM_006556.4 ENSP00000357452.3 Q15126

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000483
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000917
AC:
23
AN:
250888
Hom.:
0
AF XY:
0.0000811
AC XY:
11
AN XY:
135682
show subpopulations
Gnomad AFR exome
AF:
0.000616
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000466
Gnomad NFE exome
AF:
0.0000705
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000623
AC:
91
AN:
1461576
Hom.:
0
Cov.:
31
AF XY:
0.0000674
AC XY:
49
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.000358
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000244
Gnomad4 NFE exome
AF:
0.0000495
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000210
AC:
32
AN:
152326
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000110
Hom.:
0
Bravo
AF:
0.000227
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000988
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 26, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.391G>A (p.V131I) alteration is located in exon 4 (coding exon 4) of the PMVK gene. This alteration results from a G to A substitution at nucleotide position 391, causing the valine (V) at amino acid position 131 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Porokeratosis 1, Mibelli type Benign:1
Oct 18, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
11
DANN
Uncertain
0.99
DEOGEN2
Benign
0.18
T
Eigen
Benign
0.018
Eigen_PC
Benign
0.017
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.095
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.88
L
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.22
N
REVEL
Benign
0.14
Sift
Benign
0.38
T
Sift4G
Benign
0.86
T
Polyphen
0.93
P
Vest4
0.16
MVP
0.14
MPC
0.37
ClinPred
0.028
T
GERP RS
4.6
Varity_R
0.31
gMVP
0.41

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: rs151267286; hg19: chr1-154898881; COSMIC: COSV63785588; API