rs1555257073

chr13-28672406-CTA-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_015932.6(POMP):c.334_335del(p.Ile112TrpfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POMP NM_015932.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.49

Genes affected

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.218 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-28672406-CTA-C is Pathogenic according to our data. Variant chr13-28672406-CTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 522801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMP	NM_015932.6	c.334_335del	p.Ile112TrpfsTer3	frameshift_variant	5/6	ENST00000380842.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMP	ENST00000380842.5	c.334_335del	p.Ile112TrpfsTer3	frameshift_variant	5/6	1	NM_015932.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Feb 14, 2017	This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID: 18414213) and was found de novo in a 2-year-old male with seizure-like movements, B-lymphocyte immunodeficiency, thrombocytopenia, anemia, eosinophilia, hypogammaglobulinemia, dermatosis, and skin anomalies suggestive of Sweet syndrome. This individual has been reported in PMID: 29805043 (individual B). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 17, 2018	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555257073; hg19: chr13-29246543;