chr1-154929156-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006556.4(PMVK):​c.180G>T​(p.Gln60His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,838 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PMVK
NM_006556.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.927
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27206802).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMVKNM_006556.4 linkuse as main transcriptc.180G>T p.Gln60His missense_variant 3/5 ENST00000368467.4
PMVKNM_001323011.3 linkuse as main transcriptc.138G>T p.Gln46His missense_variant 3/5
PMVKNM_001323012.3 linkuse as main transcriptc.-46G>T 5_prime_UTR_variant 3/5
PMVKNM_001348696.2 linkuse as main transcriptc.54-99G>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMVKENST00000368467.4 linkuse as main transcriptc.180G>T p.Gln60His missense_variant 3/51 NM_006556.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461838
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 12, 2023The c.180G>T (p.Q60H) alteration is located in exon 3 (coding exon 3) of the PMVK gene. This alteration results from a G to T substitution at nucleotide position 180, causing the glutamine (Q) at amino acid position 60 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
T
Eigen
Benign
0.067
Eigen_PC
Benign
0.16
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.0064
T
MetaRNN
Benign
0.27
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
0.96
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.094
Sift
Uncertain
0.018
D
Sift4G
Benign
0.082
T
Polyphen
0.28
B
Vest4
0.20
MutPred
0.56
Gain of catalytic residue at L62 (P = 0.0654);
MVP
0.38
MPC
0.39
ClinPred
0.79
D
GERP RS
3.9
Varity_R
0.42
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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: rs1210128840; hg19: chr1-154901632; API