rs794728008

Positions:

• chr19-33463987-C-CTCACGGTGGGCCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000244137.12(PEPD):​c.623_624insAGGCCCACCGTGA​(p.Val209GlyfsTer4) variant causes a stop gained, frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEPD ENST00000244137.12 stop_gained, frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.04

Genes affected

PEPD (HGNC:8840): (peptidase D) This gene encodes a member of the peptidase family. The protein forms a homodimer that hydrolyzes dipeptides or tripeptides with C-terminal proline or hydroxyproline residues. The enzyme serves an important role in the recycling of proline, and may be rate limiting for the production of collagen. Mutations in this gene result in prolidase deficiency, which is characterized by the excretion of large amount of di- and tri-peptides containing proline. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-33463987-C-CTCACGGTGGGCCT is Pathogenic according to our data. Variant chr19-33463987-C-CTCACGGTGGGCCT is described in ClinVar as [Pathogenic]. Clinvar id is 217.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEPD	NM_000285.4	c.623_624insAGGCCCACCGTGA	p.Val209GlyfsTer4	stop_gained, frameshift_variant, splice_region_variant	8/15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166057.2	c.431_432insAGGCCCACCGTGA	p.Val145GlyfsTer4	stop_gained, frameshift_variant, splice_region_variant	6/13		NP_001159529.1
PEPD	NM_001166056.2	c.548+14058_548+14059insAGGCCCACCGTGA		intron_variant			NP_001159528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.623_624insAGGCCCACCGTGA	p.Val209GlyfsTer4	stop_gained, frameshift_variant, splice_region_variant	8/15	1	NM_000285.4	ENSP00000244137	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454254 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723574

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2023

This sequence change creates a premature translational stop signal (p.Val209Glyfs*4) in the PEPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEPD are known to be pathogenic (PMID: 8198124, 10721675, 12384772, 17142620). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Prolidase deficiency (PMID: 17142620). ClinVar contains an entry for this variant (Variation ID: 217). For these reasons, this variant has been classified as Pathogenic. -

Prolidase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2006

- -

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: rs794728008; hg19: chr19-33954893;