rs17569

Variant names:

• chr19-33391316-G-A
• rs17569
• NM_000285.4:c.1131C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-33391316-G-A
• chr19-33391316-G-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.1131C>T​(p.His377His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,610,930 control chromosomes in the GnomAD database, including 18,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1256 hom., cov: 34)
  • Exomes 𝑓: 0.15 (17039 hom.)
• Consequence: PEPD NM_000285.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.612
• Publications: 24 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=-0.52).
• BP6: Variant 19-33391316-G-A is Benign according to our data. Variant chr19-33391316-G-A is described in ClinVar as Benign. ClinVar VariationId is 328799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.612 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4	c.1131C>T	p.His377His	synonymous_variant	Exon 13 of 15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2	c.1008C>T	p.His336His	synonymous_variant	Exon 11 of 13		NP_001159528.1
PEPD	NM_001166057.2	c.939C>T	p.His313His	synonymous_variant	Exon 11 of 13		NP_001159529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.1131C>T	p.His377His	synonymous_variant	Exon 13 of 15	1	NM_000285.4	ENSP00000244137.5

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16606 AN: 152082 Hom.: 1255 Cov.: 34

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.129 AC: 31540 AN: 243920 AF XY: 0.132

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.148 AC: 215804 AN: 1458730 Hom.: 17039 Cov.: 34 AF XY: 0.147 AC XY: 106752 AN XY: 725504

African (AFR) AF: 0.0222 AC: 741 AN: 33450

American (AMR) AF: 0.0751 AC: 3344 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3180 AN: 26056

East Asian (EAS) AF: 0.246 AC: 9752 AN: 39656

South Asian (SAS) AF: 0.104 AC: 8973 AN: 85898

European-Finnish (FIN) AF: 0.130 AC: 6798 AN: 52218

Middle Eastern (MID) AF: 0.122 AC: 704 AN: 5764

European-Non Finnish (NFE) AF: 0.156 AC: 173815 AN: 1110856

Other (OTH) AF: 0.141 AC: 8497 AN: 60298

GnomAD4 genome AF: 0.109 AC: 16598 AN: 152200 Hom.: 1256 Cov.: 34 AF XY: 0.106 AC XY: 7897 AN XY: 74406

African (AFR) AF: 0.0264 AC: 1098 AN: 41554

American (AMR) AF: 0.0740 AC: 1132 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 418 AN: 3472

East Asian (EAS) AF: 0.221 AC: 1140 AN: 5152

South Asian (SAS) AF: 0.0962 AC: 464 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1392 AN: 10600

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10595 AN: 67984

Other (OTH) AF: 0.111 AC: 234 AN: 2112

Alfa AF: 0.135 Hom.: 2013

Bravo AF: 0.102

Asia WGS AF: 0.149 AC: 516 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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: MAF -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Prolidase deficiency Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 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	-0.52
CADD	Benign	8.0
DANN	Benign	0.74
PhyloP100		0.61
Mutation Taster		=97/3	polymorphism (auto)

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: rs17569; hg19: chr19-33882222; COSMIC: COSV54887682; COSMIC: COSV54887682;