chr19-33387292-A-G

Position:

• chr19-33387292-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000285.4(PEPD):​c.*52T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,608,048 control chromosomes in the GnomAD database, including 53,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6489 hom., cov: 33)
  • Exomes 𝑓: 0.25 (46923 hom.)
• Consequence: PEPD NM_000285.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.06

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-33387292-A-G is Benign according to our data. Variant chr19-33387292-A-G is described in ClinVar as [Benign]. Clinvar id is 328781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEPD	NM_000285.4	c.*52T>C		3_prime_UTR_variant	15/15	ENST00000244137.12
PEPD	NM_001166056.2	c.*52T>C		3_prime_UTR_variant	13/13
PEPD	NM_001166057.2	c.*52T>C		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEPD	ENST00000244137.12	c.*52T>C		3_prime_UTR_variant	15/15	1	NM_000285.4	P1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42871 AN: 151958 Hom.: 6480 Cov.: 33

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.250 AC: 363905 AN: 1455972 Hom.: 46923 Cov.: 31 AF XY: 0.247 AC XY: 178695 AN XY: 723860

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.282 AC: 42900 AN: 152076 Hom.: 6489 Cov.: 33 AF XY: 0.277 AC XY: 20611 AN XY: 74340

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.257

Alfa AF: 0.252 Hom.: 5036

Bravo AF: 0.287

Asia WGS AF: 0.186 AC: 646 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

Prolidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1061338; hg19: chr19-33878198; COSMIC: COSV52287281; COSMIC: COSV52287281;