1-154925080-GCC-GCCCCCCCCCCCCCCCC

Variant names:

• chr1-154925080-G-GCCCCCCCCCCCCCC
• rs112859764
• NM_006556.4:c.*48_*49insGGGGGGGGGGGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006556.4(PMVK):​c.*48_*49insGGGGGGGGGGGGGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,313,208 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PMVK NM_006556.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00600
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• porokeratosis of Mibelli

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

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006556.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMVK	NM_006556.4	MANE Select	c.*48_*49insGGGGGGGGGGGGGG		3_prime_UTR	Exon 5 of 5	NP_006547.1	Q6FGV9
	PMVK	NM_001323011.3		c.*48_*49insGGGGGGGGGGGGGG		3_prime_UTR	Exon 5 of 5	NP_001309940.1
	PMVK	NM_001323012.3		c.*48_*49insGGGGGGGGGGGGGG		3_prime_UTR	Exon 5 of 5	NP_001309941.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMVK	ENST00000368467.4	TSL:1 MANE Select	c.*48_*49insGGGGGGGGGGGGGG		3_prime_UTR	Exon 5 of 5	ENSP00000357452.3	Q15126
	PMVK	ENST00000940351.1		c.*48_*49insGGGGGGGGGGGGGG		3_prime_UTR	Exon 6 of 6	ENSP00000610410.1
	PMVK	ENST00000885059.1		c.*48_*49insGGGGGGGGGGGGGG		3_prime_UTR	Exon 6 of 6	ENSP00000555118.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.0000129 AC: 17 AN: 1313208 Hom.: 0 Cov.: 22 AF XY: 0.0000184 AC XY: 12 AN XY: 651346

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27606

American (AMR) AF: 0.000122 AC: 5 AN: 41024

Ashkenazi Jewish (ASJ) AF: 0.0000466 AC: 1 AN: 21450

East Asian (EAS) AF: 0.0000321 AC: 1 AN: 31120

South Asian (SAS) AF: 0.0000247 AC: 2 AN: 80818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5030

European-Non Finnish (NFE) AF: 0.00000495 AC: 5 AN: 1009382

Other (OTH) AF: 0.0000578 AC: 3 AN: 51912

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000304161), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0060

Splicing

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

Other links and lift over

dbSNP: rs112859764; hg19: chr1-154897556;