rs794728008

Variant names:

• chr19-33463987-C-CTCACGGTGGGCCT
• rs794728008
• NM_000285.4:c.611_623dupAGGCCCACCGTGA

Variant summary

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

The NM_000285.4(PEPD):​c.611_623dupAGGCCCACCGTGA​(p.Val209GlyfsTer4) variant causes a frameshift, stop gained, 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 NM_000285.4 frameshift, stop_gained, 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 rank	MANE	Protein	UniProt
PEPD	NM_000285.4	c.611_623dupAGGCCCACCGTGA	p.Val209GlyfsTer4	frameshift_variant, stop_gained, splice_region_variant	Exon 8 of 15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166057.2	c.419_431dupAGGCCCACCGTGA	p.Val145GlyfsTer4	frameshift_variant, stop_gained, splice_region_variant	Exon 6 of 13		NP_001159529.1
PEPD	NM_001166056.2	c.548+14046_548+14058dupAGGCCCACCGTGA		intron_variant	Intron 7 of 12		NP_001159528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.611_623dupAGGCCCACCGTGA	p.Val209GlyfsTer4	frameshift_variant, stop_gained, splice_region_variant	Exon 8 of 15	1	NM_000285.4	ENSP00000244137.5

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

May 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217). This premature translational stop signal has been observed in individual(s) with Prolidase deficiency (PMID: 17142620). This variant is not present in population databases (gnomAD no frequency). -

Prolidase deficiency Pathogenic:1

Dec 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;