rs112368783

chr13-28659088-TC-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000689222.1(ENSG00000289569):n.3del variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,547,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ENST00000689222.1 non_coding_transcript_exon
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.10

Genes affected

(HGNC:):

POMP (HGNC:20330): (proteasome maturation protein) The protein encoded by this gene is a molecular chaperone that binds 20S preproteasome components and is essential for 20S proteasome formation. The 20S proteasome is the proteolytically active component of the 26S proteasome complex. The encoded protein is degraded before the maturation of the 20S proteasome is complete. A variant in the 5' UTR of this gene has been associated with KLICK syndrome, a rare skin disorder.[provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMP	NM_015932.6			upstream_gene_variant		ENST00000380842.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000689222.1	n.3del		non_coding_transcript_exon_variant	1/1
POMP	ENST00000380842.5			upstream_gene_variant		1	NM_015932.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 153 AN: 1395050 Hom.: 0 Cov.: 29 AF XY: 0.000109 AC XY: 75 AN XY: 688556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000793

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 09, 2010

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2023

For these reasons, this variant has been classified as Pathogenic. This variant occurs in a non-coding region of the POMP gene. It does not change the encoded amino acid sequence of the POMP protein. This variant is present in population databases (rs112368783, gnomAD 0.01%). This variant has been observed in individuals with keratosis linearis with ichthyosis congenita and sclerosis keratoderma (KLICK) syndrome (PMID: 20226437, 27503413). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 116). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects POMP function (PMID: 22235297). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs112368783; hg19: chr13-29233225;