rs1555257076

Variant names:

• chr13-28672416-TGAGGAT-ACC
• rs1555257076
• NM_015932.6:c.342_348delTGAGGATinsACC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_015932.6(POMP):​c.342_348delTGAGGATinsACC​(p.Phe114LeufsTer18) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POMP NM_015932.6 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.92
• Publications: 0 publications found

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]

POMP Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 0.197 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 13-28672416-TGAGGAT-ACC is Pathogenic according to our data. Variant chr13-28672416-TGAGGAT-ACC is described in ClinVar as Pathogenic. ClinVar VariationId is 548960.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015932.6. 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
	POMP	NM_015932.6	MANE Select	c.342_348delTGAGGATinsACC	p.Phe114LeufsTer18	frameshift missense	Exon 5 of 6	NP_057016.1	Q9Y244

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMP	ENST00000380842.5	TSL:1 MANE Select	c.342_348delTGAGGATinsACC	p.Phe114LeufsTer18	frameshift missense	Exon 5 of 6	ENSP00000370222.4	Q9Y244
	POMP	ENST00000697718.1		c.342_348delTGAGGATinsACC	p.Phe114LeufsTer52	frameshift missense	Exon 5 of 6	ENSP00000513416.1	A0A8V8TLM3
	POMP	ENST00000883662.1		c.336_342delTGAGGATinsACC	p.Phe112LeufsTer18	frameshift missense	Exon 5 of 6	ENSP00000553721.1

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

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Proteasome-associated autoinflammatory syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=6/194	disease causing

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555257076;

hg19: chr13-29246553;