chr19-33387931-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000285.4(PEPD):c.1303C>T(p.Leu435Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,594,290 control chromosomes in the GnomAD database, including 55,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L435L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.30 ( 7715 hom., cov: 34)

Exomes 𝑓: 0.25 ( 47495 hom. )

Consequence

PEPD
NM_000285.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.70

Publications

45 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.922087E-4).

BP6

Variant 19-33387931-G-A is Benign according to our data. Variant chr19-33387931-G-A is described in ClinVar as Benign. ClinVar VariationId is 328791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000285.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PEPD	NM_000285.4	MANE Select	c.1303C>T	p.Leu435Phe	missense	Exon 14 of 15	NP_000276.2
PEPD	NM_001166056.2		c.1180C>T	p.Leu394Phe	missense	Exon 12 of 13	NP_001159528.1
PEPD	NM_001166057.2		c.1111C>T	p.Leu371Phe	missense	Exon 12 of 13	NP_001159529.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PEPD	ENST00000244137.12	TSL:1 MANE Select	c.1303C>T	p.Leu435Phe	missense	Exon 14 of 15	ENSP00000244137.5
PEPD	ENST00000651901.2		c.1303C>T	p.Leu435Phe	missense	Exon 14 of 16	ENSP00000498922.2
PEPD	ENST00000588328.7	TSL:3	c.1369C>T	p.Leu457Phe	missense	Exon 15 of 16	ENSP00000468516.4

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45870

AN:

152108

Hom.:

7707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.284

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.272

GnomAD2 exomes

AF:

0.229

AC:

48307

AN:

211038

AF XY:

0.225

show subpopulations

Gnomad AFR exome

AF:

0.457

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.279

Gnomad EAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.243

Gnomad OTH exome

AF:

0.236

GnomAD4 exome

AF:

0.252

AC:

362971

AN:

1442064

Hom.:

47495

Cov.:

AF XY:

0.248

AC XY:

177537

AN XY:

715260

show subpopulations

African (AFR)

AF:

0.482

AC:

16010

AN:

33232

American (AMR)

AF:

0.173

AC:

7262

AN:

41948

Ashkenazi Jewish (ASJ)

AF:

0.283

AC:

7284

AN:

25766

East Asian (EAS)

AF:

0.172

AC:

6709

AN:

38948

South Asian (SAS)

AF:

0.153

AC:

12740

AN:

83284

European-Finnish (FIN)

AF:

0.242

AC:

12273

AN:

50646

Middle Eastern (MID)

AF:

0.246

AC:

1407

AN:

5708

European-Non Finnish (NFE)

AF:

0.258

AC:

284377

AN:

1102920

Other (OTH)

AF:

0.250

AC:

14909

AN:

59612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

15399

30798

46198

61597

76996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9730

19460

29190

38920

48650

<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:

0.302

AC:

45911

AN:

152226

Hom.:

7715

Cov.:

AF XY:

0.296

AC XY:

22024

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.461

AC:

19163

AN:

41532

American (AMR)

AF:

0.210

AC:

3211

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.284

AC:

987

AN:

3470

East Asian (EAS)

AF:

0.196

AC:

1010

AN:

5158

South Asian (SAS)

AF:

0.154

AC:

741

AN:

4826

European-Finnish (FIN)

AF:

0.254

AC:

2692

AN:

10602

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.255

AC:

17320

AN:

68010

Other (OTH)

AF:

0.270

AC:

570

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1635

3270

4905

6540

8175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.260

Hom.:

10977

Bravo

AF:

0.309

TwinsUK

AF:

0.262

AC:

971

ALSPAC

AF:

0.254

AC:

980

ESP6500AA

AF:

0.397

AC:

1543

ESP6500EA

AF:

0.240

AC:

1977

ExAC

AF:

0.213

AC:

25299

Asia WGS

AF:

0.192

AC:

670

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Prolidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.19

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.079

MetaRNN

Benign

0.00099

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.96

PhyloP100

2.7

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

REVEL

Benign

0.28

Sift

Benign

0.84

Sift4G

Benign

0.54

Polyphen

0.0010

Vest4

0.046

MPC

0.12

ClinPred

0.011

GERP RS

3.4

Varity_R

0.27

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over