1-154925080-GCC-GCCCCCCCC

Variant names:

• chr1-154925080-G-GCCCCCC
• rs112859764
• NM_006556.4:c.*48_*49insGGGGGG

Variant summary

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

The NM_006556.4(PMVK):​c.*48_*49insGGGGGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,313,114 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.00019 (1 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_*49insGGGGGG		3_prime_UTR	Exon 5 of 5	NP_006547.1	Q6FGV9
	PMVK	NM_001323011.3		c.*48_*49insGGGGGG		3_prime_UTR	Exon 5 of 5	NP_001309940.1
	PMVK	NM_001323012.3		c.*48_*49insGGGGGG		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_*49insGGGGGG		3_prime_UTR	Exon 5 of 5	ENSP00000357452.3	Q15126
	PMVK	ENST00000940351.1		c.*48_*49insGGGGGG		3_prime_UTR	Exon 6 of 6	ENSP00000610410.1
	PMVK	ENST00000885059.1		c.*48_*49insGGGGGG		3_prime_UTR	Exon 6 of 6	ENSP00000555118.1

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 145954 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000338 AC: 81 AN: 239750 AF XY: 0.000301

Gnomad AFR exome AF: 0.000320

Gnomad AMR exome AF: 0.000823

Gnomad ASJ exome AF: 0.000314

Gnomad EAS exome AF: 0.000515

Gnomad FIN exome AF: 0.000207

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.000689

GnomAD4 exome AF: 0.000191 AC: 251 AN: 1313114 Hom.: 1 Cov.: 22 AF XY: 0.000192 AC XY: 125 AN XY: 651298

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

African (AFR) AF: 0.000326 AC: 9 AN: 27602

American (AMR) AF: 0.00119 AC: 49 AN: 41006

Ashkenazi Jewish (ASJ) AF: 0.000420 AC: 9 AN: 21444

East Asian (EAS) AF: 0.000193 AC: 6 AN: 31118

South Asian (SAS) AF: 0.000520 AC: 42 AN: 80794

European-Finnish (FIN) AF: 0.000201 AC: 9 AN: 44868

Middle Eastern (MID) AF: 0.000199 AC: 1 AN: 5030

European-Non Finnish (NFE) AF: 0.000110 AC: 111 AN: 1009346

Other (OTH) AF: 0.000289 AC: 15 AN: 51906

⚠️ 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: 145954 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 70732

⚠️ 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: 38816

American (AMR) AF: 0.00 AC: 0 AN: 14146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

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: 0.0000149 AC: 1 AN: 67090

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.

Alfa AF: 0.000143 Hom.: 10

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;