rs3745969

chr19-33463006-A-G

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.660T>C(p.Tyr220=) 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:4
• Conservation: PhyloP100: 0.456

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=-0.59).
• BP6: Variant 19-33463006-A-G is Benign according to our data. Variant chr19-33463006-A-G is described in ClinVar as [Benign]. Clinvar id is 328812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33463006-A-G is described in Lovd as [Benign]. Variant chr19-33463006-A-G is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
PEPD	NM_000285.4	c.660T>C	p.Tyr220=	synonymous_variant	9/15	ENST00000244137.12
PEPD	NM_001166057.2	c.468T>C	p.Tyr156=	synonymous_variant	7/13
PEPD	NM_001166056.2	c.548+15040T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEPD	ENST00000244137.12	c.660T>C	p.Tyr220=	synonymous_variant	9/15	1	NM_000285.4	P1

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

GnomAD3 exomes AF: 0.0380 AC: 9480 AN: 249576 Hom.: 335 AF XY: 0.0388 AC XY: 5260 AN XY: 135404

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 SAS exome AF: 0.0351

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

Gnomad4 AFR exome AF: 0.00461

Gnomad4 AMR exome AF: 0.00845

Gnomad4 ASJ exome AF: 0.0214

Gnomad4 EAS exome AF: 0.0841

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0319

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

Gnomad4 AFR AF: 0.00618

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.0773

Gnomad4 SAS AF: 0.0346

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.0338

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0304 Hom.: 48

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

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: Frequency -

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	-0.59
Cadd	Benign	7.4
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs3745969; hg19: chr19-33953912; COSMIC: COSV54887695;