rs139248801

chr1-154929049-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006556.4(PMVK):c.287T>C(p.Val96Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00596 in 1,614,132 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: PMVK NM_006556.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.99

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008589804).
• BP6: Variant 1-154929049-A-G is Benign according to our data. Variant chr1-154929049-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 377095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 664 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMVK	NM_006556.4	c.287T>C	p.Val96Ala	missense_variant	3/5	ENST00000368467.4
PMVK	NM_001323011.3	c.245T>C	p.Val82Ala	missense_variant	3/5
PMVK	NM_001323012.3	c.62T>C	p.Val21Ala	missense_variant	3/5
PMVK	NM_001348696.2	c.62T>C	p.Val21Ala	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMVK	ENST00000368467.4	c.287T>C	p.Val96Ala	missense_variant	3/5	1	NM_006556.4	P1

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 664 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00748

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00431 AC: 1083 AN: 251470 Hom.: 6 AF XY: 0.00433 AC XY: 589 AN XY: 135910

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00612 AC: 8953 AN: 1461844 Hom.: 32 Cov.: 31 AF XY: 0.00605 AC XY: 4398 AN XY: 727224

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00739

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.00436 AC: 664 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74470

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00747

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00640 Hom.: 8

Bravo AF: 0.00454

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00518 AC: 629

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Nov 07, 2016

- -

PMVK-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.083
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.67	P
Vest4		0.61
MVP		0.39
MPC		0.92
ClinPred		0.025	T
GERP RS		5.9
Varity_R		0.41
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs139248801; hg19: chr1-154901525; COSMIC: COSV100870502;