chr1-154932364-T-C

Position:

• chr1-154932364-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006556.4(PMVK):​c.147A>G​(p.Glu49=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0897 in 1,612,024 control chromosomes in the GnomAD database, including 16,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (7368 hom., cov: 32)
  • Exomes 𝑓: 0.077 (9538 hom.)
• Consequence: PMVK NM_006556.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0670

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-154932364-T-C is Benign according to our data. Variant chr1-154932364-T-C is described in ClinVar as [Benign]. Clinvar id is 1278538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.067 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMVK	NM_006556.4	c.147A>G	p.Glu49=	synonymous_variant	2/5	ENST00000368467.4
PMVK	NM_001348696.2	c.41A>G	p.Asn14Ser	missense_variant	2/5
PMVK	NM_001323011.3	c.105A>G	p.Glu35=	synonymous_variant	2/5
PMVK	NM_001323012.3	c.-79A>G		5_prime_UTR_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMVK	ENST00000368467.4	c.147A>G	p.Glu49=	synonymous_variant	2/5	1	NM_006556.4	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31427 AN: 151924 Hom.: 7325 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0977

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.0656

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.0953 AC: 23888 AN: 250722 Hom.: 3411 AF XY: 0.0861 AC XY: 11671 AN XY: 135558

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.0643

Gnomad EAS exome AF: 0.000816

Gnomad SAS exome AF: 0.0689

Gnomad FIN exome AF: 0.0583

Gnomad NFE exome AF: 0.0686

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0774 AC: 113004 AN: 1459984 Hom.: 9538 Cov.: 29 AF XY: 0.0752 AC XY: 54633 AN XY: 726388

Gnomad4 AFR exome AF: 0.604

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0652

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0693

Gnomad4 FIN exome AF: 0.0573

Gnomad4 NFE exome AF: 0.0655

Gnomad4 OTH exome AF: 0.0971

GnomAD4 genome AF: 0.207 AC: 31522 AN: 152040 Hom.: 7368 Cov.: 32 AF XY: 0.201 AC XY: 14948 AN XY: 74312

Gnomad4 AFR AF: 0.581

Gnomad4 AMR AF: 0.0975

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0608

Gnomad4 FIN AF: 0.0559

Gnomad4 NFE AF: 0.0656

Gnomad4 OTH AF: 0.159

Alfa AF: 0.0929 Hom.: 3663

Bravo AF: 0.225

Asia WGS AF: 0.0930 AC: 323 AN: 3478

EpiCase AF: 0.0639

EpiControl AF: 0.0671

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	- -

PMVK-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 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
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.7
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs1891805; hg19: chr1-154904840; COSMIC: COSV63785879;