rs3745969

Variant names:

• chr19-33463006-A-G
• rs3745969
• NM_000285.4:c.660T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000285.4(PEPD):​c.660T>C​(p.Tyr220Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,596,230 control chromosomes in the GnomAD database, including 1,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (148 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1330 hom.)
• Consequence: PEPD NM_000285.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.456
• Publications: 8 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 19-33463006-A-G is Benign according to our data. Variant chr19-33463006-A-G is described in ClinVar as Benign. ClinVar VariationId is 328812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.456 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4	c.660T>C	p.Tyr220Tyr	synonymous_variant	Exon 9 of 15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166057.2	c.468T>C	p.Tyr156Tyr	synonymous_variant	Exon 7 of 13		NP_001159529.1
PEPD	NM_001166056.2	c.548+15040T>C		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.660T>C	p.Tyr220Tyr	synonymous_variant	Exon 9 of 15	1	NM_000285.4	ENSP00000244137.5

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4807 AN: 152124 Hom.: 149 Cov.: 33

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0771

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0380 AC: 9480 AN: 249576 AF XY: 0.0388

Gnomad AFR exome AF: 0.00562

Gnomad AMR exome AF: 0.00796

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.0732

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0370 AC: 53357 AN: 1443988 Hom.: 1330 Cov.: 27 AF XY: 0.0371 AC XY: 26665 AN XY: 719600

African (AFR) AF: 0.00461 AC: 153 AN: 33170

American (AMR) AF: 0.00845 AC: 378 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 558 AN: 26038

East Asian (EAS) AF: 0.0841 AC: 3333 AN: 39628

South Asian (SAS) AF: 0.0361 AC: 3102 AN: 85916

European-Finnish (FIN) AF: 0.113 AC: 6054 AN: 53384

Middle Eastern (MID) AF: 0.0150 AC: 86 AN: 5744

European-Non Finnish (NFE) AF: 0.0345 AC: 37784 AN: 1095642

Other (OTH) AF: 0.0319 AC: 1909 AN: 59754

GnomAD4 genome AF: 0.0316 AC: 4808 AN: 152242 Hom.: 148 Cov.: 33 AF XY: 0.0348 AC XY: 2589 AN XY: 74436

African (AFR) AF: 0.00618 AC: 257 AN: 41554

American (AMR) AF: 0.0139 AC: 213 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.0773 AC: 401 AN: 5188

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4830

European-Finnish (FIN) AF: 0.121 AC: 1280 AN: 10574

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0338 AC: 2297 AN: 68018

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0326 Hom.: 164

Bravo AF: 0.0234

Asia WGS AF: 0.0600 AC: 207 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0302

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Prolidase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.59
CADD	Benign	7.4
DANN	Benign	0.42
PhyloP100		0.46
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.060		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: rs3745969; hg19: chr19-33953912; COSMIC: COSV54887695;