Genetic Variant PEPD:c.671+21586A>G (chr19-33441409-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000285.4(PEPD):c.671+21586A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 152,016 control chromosomes in the GnomAD database, including 24,568 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.56 ( 24568 hom., cov: 32)

Consequence

PEPD
NM_000285.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.444

Publications

10 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

PEPD links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 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	Effect	Exon Rank	Protein	UniProt
PEPD	NM_000285.4	MANE Select	c.671+21586A>G	intron	N/A	NP_000276.2	A0A140VJR2
PEPD	NM_001166056.2		c.549-27766A>G	intron	N/A	NP_001159528.1	P12955-2
PEPD	NM_001166057.2		c.479+21586A>G	intron	N/A	NP_001159529.1	P12955-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PEPD	ENST00000244137.12	TSL:1 MANE Select	c.671+21586A>G	intron	N/A	ENSP00000244137.5	P12955-1
PEPD	ENST00000651901.2		c.671+21586A>G	intron	N/A	ENSP00000498922.2	A0A494C165
PEPD	ENST00000588328.7	TSL:3	c.671+21586A>G	intron	N/A	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes

AF:

0.561

AC:

85206

AN:

151898

Hom.:

24534

Cov.:

show subpopulations

Gnomad AFR

AF:

0.651

Gnomad AMI

AF:

0.474

Gnomad AMR

AF:

0.407

Gnomad ASJ

AF:

0.516

Gnomad EAS

AF:

0.420

Gnomad SAS

AF:

0.407

Gnomad FIN

AF:

0.482

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.579

Gnomad OTH

AF:

0.534

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.561

AC:

85282

AN:

152016

Hom.:

24568

Cov.:

AF XY:

0.552

AC XY:

40984

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.651

AC:

26997

AN:

41472

American (AMR)

AF:

0.406

AC:

6204

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.516

AC:

1789

AN:

3470

East Asian (EAS)

AF:

0.421

AC:

2167

AN:

5144

South Asian (SAS)

AF:

0.407

AC:

1957

AN:

4808

European-Finnish (FIN)

AF:

0.482

AC:

5094

AN:

10566

Middle Eastern (MID)

AF:

0.524

AC:

153

AN:

292

European-Non Finnish (NFE)

AF:

0.579

AC:

39373

AN:

67960

Other (OTH)

AF:

0.528

AC:

1117

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1944

3888

5831

7775

9719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<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:

0.569

Hom.:

75409

Bravo

AF:

0.562

Asia WGS

AF:

0.423

AC:

1475

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Benign

0.38

PhyloP100

0.44

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over