rs745834191

Variant names:

• chr19-33413620-GAGT-G
• rs745834191
• NM_000285.4:c.692_694delACT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM4_Supporting PP5_Very_Strong

The NM_000285.4(PEPD):​c.692_694delACT​(p.Tyr231del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,589,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000411470: Functional studies in cultured fibroblasts from these two individuals showed significantly decreased prolidase enzyme expression and activity compared to control fibroblasts (Lupi et al. 2004" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y231Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PEPD NM_000285.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.28
• Publications: 5 publications found

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]

PEPD Gene-Disease associations (from GenCC):

• prolidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000411470: Functional studies in cultured fibroblasts from these two individuals showed significantly decreased prolidase enzyme expression and activity compared to control fibroblasts (Lupi et al. 2004; Besio et al. 2013). Besio et al. (2013) demonstrated the variant resulted in reduced thermal stability, low catalytic efficiency and impaired Mn(II) cofactor binding of PEPD.; SCV002260970: Experimental studies have shown that this variant affects PEPD function (PMID: 23516557).; SCV005077985: Published functional studies demonstrate that this variant significantly reduces enzyme activity compared to wildtype (Lupi et al., 2004; Besio et al., 2013); SCV005352814: Prolidase activity was significantly reduced in patient fibroblasts carrying the homozygous p.Tyr231del variant, and recombinant p.Tyr231del protein showed loss of catalytic efficiency, thermal instability, and changes in protein confirmation (described as 231delY in Besio et al. 2013. PubMed ID: 23516557).
• PM4: Nonframeshift variant in NON repetitive region in NM_000285.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-33413620-GAGT-G is Pathogenic according to our data. Variant chr19-33413620-GAGT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 328810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000285.4. 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
	PEPD	NM_000285.4	MANE Select	c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 15	NP_000276.2	A0A140VJR2
	PEPD	NM_001166056.2		c.569_571delACT	p.Tyr190del	disruptive_inframe_deletion	Exon 8 of 13	NP_001159528.1	P12955-2
	PEPD	NM_001166057.2		c.500_502delACT	p.Tyr167del	disruptive_inframe_deletion	Exon 8 of 13	NP_001159529.1	P12955-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEPD	ENST00000244137.12	TSL:1 MANE Select	c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 15	ENSP00000244137.5	P12955-1
	PEPD	ENST00000651901.2		c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 16	ENSP00000498922.2	A0A494C165
	PEPD	ENST00000588328.7	TSL:3	c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 16	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 34 AN: 208060 AF XY: 0.000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000241

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.000188 AC: 270 AN: 1436872 Hom.: 0 AF XY: 0.000166 AC XY: 118 AN XY: 712412

African (AFR) AF: 0.0000605 AC: 2 AN: 33046

American (AMR) AF: 0.000335 AC: 14 AN: 41840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25664

East Asian (EAS) AF: 0.00 AC: 0 AN: 38574

South Asian (SAS) AF: 0.00 AC: 0 AN: 82284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.000218 AC: 240 AN: 1099300

Other (OTH) AF: 0.000236 AC: 14 AN: 59404

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74484

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Prolidase deficiency (6)
3	-	-	not provided (3)
1	-	-	PEPD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs745834191; hg19: chr19-33904526;