1-154926423-C-T

Position:

• chr1-154926423-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006556.4(PMVK):​c.373G>A​(p.Val125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,752 control chromosomes in the GnomAD database, including 1,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.059 (891 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (806 hom.)
• Consequence: PMVK NM_006556.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.957

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066597164).
• BP6: Variant 1-154926423-C-T is Benign according to our data. Variant chr1-154926423-C-T is described in ClinVar as [Benign]. Clinvar id is 1180221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMVK	NM_006556.4	c.373G>A	p.Val125Met	missense_variant	4/5	ENST00000368467.4
PMVK	NM_001323011.3	c.331G>A	p.Val111Met	missense_variant	4/5
PMVK	NM_001323012.3	c.148G>A	p.Val50Met	missense_variant	4/5
PMVK	NM_001348696.2	c.148G>A	p.Val50Met	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMVK	ENST00000368467.4	c.373G>A	p.Val125Met	missense_variant	4/5	1	NM_006556.4	P1

Frequencies

GnomAD3 genomes AF: 0.0594 AC: 9032 AN: 152150 Hom.: 890 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0170 AC: 4261 AN: 250886 Hom.: 363 AF XY: 0.0128 AC XY: 1735 AN XY: 135692

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00712 AC: 10407 AN: 1461484 Hom.: 806 Cov.: 31 AF XY: 0.00628 AC XY: 4563 AN XY: 727072

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000979

Gnomad4 OTH exome AF: 0.0155

GnomAD4 genome AF: 0.0594 AC: 9052 AN: 152268 Hom.: 891 Cov.: 32 AF XY: 0.0571 AC XY: 4254 AN XY: 74454

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.0250

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0210 Hom.: 257

Bravo AF: 0.0686

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.195 AC: 857

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.0200 AC: 2432

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00261

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.57
DANN	Benign	0.58
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.015
Sift	Benign	0.17	T
Sift4G	Benign	0.11	T
Polyphen		0.031	B
Vest4		0.092
MPC		0.43
ClinPred		0.0020	T
GERP RS		-0.86
Varity_R		0.099
gMVP		0.35

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

Other links and lift over

dbSNP: rs16836525; hg19: chr1-154898899;