1-154925080-GCC-GCCCCCCC

Variant names:

• chr1-154925080-G-GCCCCC
• rs112859764
• NM_006556.4:c.*48_*49insGGGGG

Variant summary

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

The NM_006556.4(PMVK):​c.*48_*49insGGGGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,313,170 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: 𝑓 0.0000069 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMVK NM_006556.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00600
• Publications: 2 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_*49insGGGGG		3_prime_UTR	Exon 5 of 5	NP_006547.1	Q6FGV9
	PMVK	NM_001323011.3		c.*48_*49insGGGGG		3_prime_UTR	Exon 5 of 5	NP_001309940.1
	PMVK	NM_001323012.3		c.*48_*49insGGGGG		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_*49insGGGGG		3_prime_UTR	Exon 5 of 5	ENSP00000357452.3	Q15126
	PMVK	ENST00000940351.1		c.*48_*49insGGGGG		3_prime_UTR	Exon 6 of 6	ENSP00000610410.1
	PMVK	ENST00000885059.1		c.*48_*49insGGGGG		3_prime_UTR	Exon 6 of 6	ENSP00000555118.1

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 145974 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000626 AC: 15 AN: 239750 AF XY: 0.0000462

Gnomad AFR exome AF: 0.0000641

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.000210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000373 AC: 49 AN: 1313170 Hom.: 0 Cov.: 22 AF XY: 0.0000368 AC XY: 24 AN XY: 651330

⚠️ 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: 27604

American (AMR) AF: 0.000366 AC: 15 AN: 41016

Ashkenazi Jewish (ASJ) AF: 0.000186 AC: 4 AN: 21450

East Asian (EAS) AF: 0.00 AC: 0 AN: 31114

South Asian (SAS) AF: 0.0000866 AC: 7 AN: 80810

European-Finnish (FIN) AF: 0.0000446 AC: 2 AN: 44860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5028

European-Non Finnish (NFE) AF: 0.0000168 AC: 17 AN: 1009378

Other (OTH) AF: 0.0000771 AC: 4 AN: 51910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000685 AC: 1 AN: 145974 Hom.: 0 Cov.: 26 AF XY: 0.0000141 AC XY: 1 AN XY: 70744

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

African (AFR) AF: 0.00 AC: 0 AN: 38824

American (AMR) AF: 0.00 AC: 0 AN: 14148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 4968

South Asian (SAS) AF: 0.00 AC: 0 AN: 4680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67096

Other (OTH) AF: 0.00 AC: 0 AN: 1978

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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;