1-154925080-GCC-GCCC

Variant names:

• chr1-154925080-G-GC
• rs112859764
• NM_006556.4:c.*48dupG

Variant summary

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

The NM_006556.4(PMVK):​c.*48dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000099 in 1,313,208 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000099 (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.*48dupG		3_prime_UTR	Exon 5 of 5	NP_006547.1	Q6FGV9
	PMVK	NM_001323011.3		c.*48dupG		3_prime_UTR	Exon 5 of 5	NP_001309940.1
	PMVK	NM_001323012.3		c.*48dupG		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.*48dupG		3_prime_UTR	Exon 5 of 5	ENSP00000357452.3	Q15126
	PMVK	ENST00000940351.1		c.*48dupG		3_prime_UTR	Exon 6 of 6	ENSP00000610410.1
	PMVK	ENST00000885059.1		c.*48dupG		3_prime_UTR	Exon 6 of 6	ENSP00000555118.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000990 AC: 13 AN: 1313208 Hom.: 0 Cov.: 22 AF XY: 0.00000768 AC XY: 5 AN XY: 651354

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

African (AFR) AF: 0.0000362 AC: 1 AN: 27606

American (AMR) AF: 0.0000731 AC: 3 AN: 41022

Ashkenazi Jewish (ASJ) AF: 0.0000466 AC: 1 AN: 21448

East Asian (EAS) AF: 0.00 AC: 0 AN: 31118

South Asian (SAS) AF: 0.0000247 AC: 2 AN: 80822

European-Finnish (FIN) AF: 0.0000446 AC: 2 AN: 44868

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

European-Non Finnish (NFE) AF: 0.00000396 AC: 4 AN: 1009382

Other (OTH) AF: 0.00 AC: 0 AN: 51912

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000120014), 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

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

Other links and lift over

dbSNP: rs112859764; hg19: chr1-154897556;