1-154939322-A-G

Variant names:

• chr1-154939322-A-G
• rs4845695
• NM_001323012.3:c.-131+3254T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001323012.3(PMVK):​c.-131+3254T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 151,944 control chromosomes in the GnomAD database, including 10,945 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (10945 hom., cov: 31)
• Consequence: PMVK NM_001323012.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.626
• Publications: 12 publications found

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]

PMVK Gene-Disease associations (from GenCC):

• porokeratosis 1, Mibelli type

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• porokeratosis of Mibelli

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autoinflammatory syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMVK	NM_001323012.3	c.-131+3254T>C		intron_variant	Intron 1 of 4		NP_001309941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49760 AN: 151826 Hom.: 10948 Cov.: 31

Gnomad AFR AF: 0.0768

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.358

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.327 AC: 49754 AN: 151944 Hom.: 10945 Cov.: 31 AF XY: 0.338 AC XY: 25109 AN XY: 74252

African (AFR) AF: 0.0766 AC: 3178 AN: 41464

American (AMR) AF: 0.494 AC: 7528 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3468

East Asian (EAS) AF: 0.881 AC: 4553 AN: 5166

South Asian (SAS) AF: 0.569 AC: 2738 AN: 4810

European-Finnish (FIN) AF: 0.374 AC: 3946 AN: 10558

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25099 AN: 67938

Other (OTH) AF: 0.355 AC: 750 AN: 2112

Alfa AF: 0.361 Hom.: 6958

Bravo AF: 0.327

Asia WGS AF: 0.652 AC: 2262 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.4
DANN	Benign	0.88
PhyloP100		0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4845695; hg19: chr1-154911798;