Genetic Variant PEPD:p.Tyr231del (chr19-33413620-GAGT-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM4_SupportingPP5_Very_Strong

The NM_000285.4(PEPD):c.692_694delACT(p.Tyr231del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,589,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y231Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

PEPD
NM_000285.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.28

Publications

5 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: Likely_pathogenic. The variant received 9 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000285.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 19-33413620-GAGT-G is Pathogenic according to our data. Variant chr19-33413620-GAGT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 328810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 15	NP_000276.2
PEPD	NM_001166056.2		c.569_571delACT	p.Tyr190del	disruptive_inframe_deletion	Exon 8 of 13	NP_001159528.1
PEPD	NM_001166057.2		c.500_502delACT	p.Tyr167del	disruptive_inframe_deletion	Exon 8 of 13	NP_001159529.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PEPD	ENST00000244137.12	TSL:1 MANE Select	c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 15	ENSP00000244137.5
PEPD	ENST00000651901.2		c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 16	ENSP00000498922.2
PEPD	ENST00000588328.7	TSL:3	c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	Exon 10 of 16	ENSP00000468516.4

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

208060

AF XY:

0.000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000355

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000241

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.000188

AC:

270

AN:

1436872

Hom.:

AF XY:

0.000166

AC XY:

118

AN XY:

712412

show subpopulations

African (AFR)

AF:

0.0000605

AC:

AN:

33046

American (AMR)

AF:

0.000335

AC:

AN:

41840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25664

East Asian (EAS)

AF:

0.00

AC:

AN:

38574

South Asian (SAS)

AF:

0.00

AC:

AN:

82284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.000218

AC:

240

AN:

1099300

Other (OTH)

AF:

0.000236

AC:

AN:

59404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000138

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41576

American (AMR)

AF:

0.000392

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000217

Hom.:

Bravo

AF:

0.000159

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Prolidase deficiency (6)

not provided (3)

PEPD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=3/97

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over