19-33387291-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000285.4(PEPD):c.*53C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,608,558 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (189 hom.)
• Consequence: PEPD NM_000285.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.10

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-33387291-G-A is Benign according to our data. Variant chr19-33387291-G-A is described in ClinVar as [Benign]. Clinvar id is 328780.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEPD	NM_000285.4	c.*53C>T		3_prime_UTR_variant	15/15	ENST00000244137.12
PEPD	NM_001166056.2	c.*53C>T		3_prime_UTR_variant	13/13
PEPD	NM_001166057.2	c.*53C>T		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEPD	ENST00000244137.12	c.*53C>T		3_prime_UTR_variant	15/15	1	NM_000285.4	P1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 565 AN: 152176 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0784

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00903

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00339 AC: 4939 AN: 1456264 Hom.: 189 Cov.: 29 AF XY: 0.00334 AC XY: 2421 AN XY: 724040

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0939

Gnomad4 SAS exome AF: 0.000581

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.000337

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152294 Hom.: 11 Cov.: 33 AF XY: 0.00457 AC XY: 340 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0784

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00903

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.0270 AC: 94 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Prolidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.82
Cadd	Benign	6.2
Dann	Benign	0.56

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: rs77690463; hg19: chr19-33878197; COSMIC: COSV52287665; COSMIC: COSV52287665;