rs17570

chr19-33387931-G-Achr19-33387931-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.70

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 328791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33387931-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEPD	NM_000285.4	c.1303C>T	p.Leu435Phe	missense_variant	14/15	ENST00000244137.12
PEPD	NM_001166056.2	c.1180C>T	p.Leu394Phe	missense_variant	12/13
PEPD	NM_001166057.2	c.1111C>T	p.Leu371Phe	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEPD	ENST00000244137.12	c.1303C>T	p.Leu435Phe	missense_variant	14/15	1	NM_000285.4	P1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45870 AN: 152108 Hom.: 7707 Cov.: 34

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

GnomAD3 exomes AF: 0.229 AC: 48307 AN: 211038 Hom.: 5974 AF XY: 0.225 AC XY: 25869 AN XY: 115214

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 SAS exome AF: 0.154

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.: 34 AF XY: 0.248 AC XY: 177537 AN XY: 715260

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.302 AC: 45911 AN: 152226 Hom.: 7715 Cov.: 34 AF XY: 0.296 AC XY: 22024 AN XY: 74422

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.270

Alfa AF: 0.258 Hom.: 7519

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	19
Dann	Benign	0.35
DEOGEN2	Benign	0.19	T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.079	T;T;T
MetaRNN	Benign	0.00099	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.96	L;.;.
MutationTaster	Benign	0.96	P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.84	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.046
MPC		0.12
ClinPred		0.011	T
GERP RS		3.4
Varity_R		0.27

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

LitVar

Other links and lift over

dbSNP: rs17570; hg19: chr19-33878837; COSMIC: COSV54890582; COSMIC: COSV54890582;