chr1-154926360-T-A

Variant summary

Our verdict is Likely benign. Variant got -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. 13/21 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. 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

5
14

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.47
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 Likely_benign. Variant got -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 id is 2639382.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMVKNM_006556.4 linkuse as main transcriptc.436A>T p.Thr146Ser missense_variant 4/5 ENST00000368467.4
PMVKNM_001323011.3 linkuse as main transcriptc.394A>T p.Thr132Ser missense_variant 4/5
PMVKNM_001323012.3 linkuse as main transcriptc.211A>T p.Thr71Ser missense_variant 4/5
PMVKNM_001348696.2 linkuse as main transcriptc.211A>T p.Thr71Ser missense_variant 4/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMVKENST00000368467.4 linkuse as main transcriptc.436A>T p.Thr146Ser missense_variant 4/51 NM_006556.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152162
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250220
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135318
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 SAS 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:
3
AN:
1460758
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726688
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2022PMVK: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.34
T
Eigen
Benign
-0.087
Eigen_PC
Benign
-0.020
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.73
T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-2.8
D
REVEL
Benign
0.14
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.025
D
Polyphen
0.015
B
Vest4
0.25
MutPred
0.36
Gain of disorder (P = 0.0548);
MVP
0.38
MPC
0.38
ClinPred
0.79
D
GERP RS
3.5
Varity_R
0.30
gMVP
0.34

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: rs1350346775; hg19: chr1-154898836; API