chr19-33411746-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000285.4(PEPD):c.744T>C(p.Gly248Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,600,728 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 31 hom., cov: 33)

Exomes 𝑓: 0.017 ( 288 hom. )

Consequence

PEPD
NM_000285.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0270

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

prolidase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

PEPD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 19-33411746-A-G is Benign according to our data. Variant chr19-33411746-A-G is described in ClinVar as Benign. ClinVar VariationId is 328808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.027 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2165/152312) while in subpopulation NFE AF = 0.0172 (1167/68018). AF 95% confidence interval is 0.0163. There are 31 homozygotes in GnomAd4. There are 1183 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4 link	c.744T>C	p.Gly248Gly	synonymous_variant	Exon 11 of 15	ENST00000244137.12	NP_000276.2	P12955-1A0A140VJR2
PEPD	NM_001166056.2 link	c.621T>C	p.Gly207Gly	synonymous_variant	Exon 9 of 13		NP_001159528.1	P12955-2
PEPD	NM_001166057.2 link	c.552T>C	p.Gly184Gly	synonymous_variant	Exon 9 of 13		NP_001159529.1	P12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12 link	c.744T>C	p.Gly248Gly	synonymous_variant	Exon 11 of 15	1	NM_000285.4	ENSP00000244137.5		P12955-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2163

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0564

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0171

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.0164

AC:

4037

AN:

246478

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.00293

Gnomad AMR exome

AF:

0.00583

Gnomad ASJ exome

AF:

0.0275

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.0534

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0170

AC:

24618

AN:

1448416

Hom.:

288

Cov.:

AF XY:

0.0171

AC XY:

12364

AN XY:

721324

show subpopulations

African (AFR)

AF:

0.00244

AC:

AN:

33196

American (AMR)

AF:

0.00587

AC:

262

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

668

AN:

26010

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39642

South Asian (SAS)

AF:

0.0154

AC:

1325

AN:

85794

European-Finnish (FIN)

AF:

0.0520

AC:

2757

AN:

52994

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0168

AC:

18506

AN:

1100532

Other (OTH)

AF:

0.0159

AC:

952

AN:

59902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1125

2250

3375

4500

5625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

714

1428

2142

2856

3570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0142

AC:

2165

AN:

152312

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1183

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00313

AC:

130

AN:

41568

American (AMR)

AF:

0.00562

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0126

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0564

AC:

598

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1167

AN:

68018

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

107

213

320

426

533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.0102

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0144

EpiControl

AF:

0.0147

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.60

CADD

Benign

2.5

(source)

DANN

Benign

0.40

PhyloP100

-0.027

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over