rs3745969

Positions:

chr19-33463006-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.456

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
PEPD	NM_000285.4 linkuse as main transcript	c.660T>C	p.Tyr220=	synonymous_variant	9/15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166057.2 linkuse as main transcript	c.468T>C	p.Tyr156=	synonymous_variant	7/13		NP_001159529.1
PEPD	NM_001166056.2 linkuse as main transcript	c.548+15040T>C		intron_variant			NP_001159528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12 linkuse as main transcript	c.660T>C	p.Tyr220=	synonymous_variant	9/15	1	NM_000285.4	ENSP00000244137	P1	P12955-1

Frequencies

GnomAD3 genomes

AF:

0.0316

AC:

4807

AN:

152124

Hom.:

149

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0371

AC XY:

26665

AN XY:

719600

show subpopulations

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.:

AF XY:

0.0348

AC XY:

2589

AN XY:

74436

show subpopulations

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.:

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over