rs17569

chr19-33391316-G-Achr19-33391316-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000285.4(PEPD):c.1131C>T(p.His377=) 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:5
• Conservation: PhyloP100: 0.612

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 -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 id is 328799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33391316-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PEPD	NM_000285.4	c.1131C>T	p.His377=	synonymous_variant	13/15	ENST00000244137.12
PEPD	NM_001166056.2	c.1008C>T	p.His336=	synonymous_variant	11/13
PEPD	NM_001166057.2	c.939C>T	p.His313=	synonymous_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEPD	ENST00000244137.12	c.1131C>T	p.His377=	synonymous_variant	13/15	1	NM_000285.4	P1

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

GnomAD3 exomes AF: 0.129 AC: 31540 AN: 243920 Hom.: 2378 AF XY: 0.132 AC XY: 17542 AN XY: 133048

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 SAS exome AF: 0.102

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

Gnomad4 AFR exome AF: 0.0222

Gnomad4 AMR exome AF: 0.0751

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.141

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

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.0740

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.0962

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.111

Alfa AF: 0.142 Hom.: 1425

Bravo AF: 0.102

Asia WGS AF: 0.149 AC: 516 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Prolidase deficiency Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	8.0
Dann	Benign	0.74

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