rs2230062

Variant names:

• chr19-33388071-C-T
• rs2230062
• NM_000285.4:c.1163G>A

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.1163G>A​(p.Arg388His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,548,190 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (25 hom., cov: 34)
  • Exomes 𝑓: 0.0041 (192 hom.)
• Consequence: PEPD NM_000285.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.37

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=0.003597349).
• BP6: Variant 19-33388071-C-T is Benign according to our data. Variant chr19-33388071-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33388071-C-T is described in Lovd as [Benign]. Variant chr19-33388071-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4	c.1163G>A	p.Arg388His	missense_variant	Exon 14 of 15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2	c.1040G>A	p.Arg347His	missense_variant	Exon 12 of 13		NP_001159528.1
PEPD	NM_001166057.2	c.971G>A	p.Arg324His	missense_variant	Exon 12 of 13		NP_001159529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.1163G>A	p.Arg388His	missense_variant	Exon 14 of 15	1	NM_000285.4	ENSP00000244137.5

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 657 AN: 152190 Hom.: 25 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0918

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0101 AC: 1493 AN: 147188 Hom.: 51 AF XY: 0.0103 AC XY: 817 AN XY: 79310

Gnomad AFR exome AF: 0.000397

Gnomad AMR exome AF: 0.000527

Gnomad ASJ exome AF: 0.000474

Gnomad EAS exome AF: 0.0994

Gnomad SAS exome AF: 0.0134

Gnomad FIN exome AF: 0.00384

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00411 AC: 5738 AN: 1395882 Hom.: 192 Cov.: 32 AF XY: 0.00434 AC XY: 2990 AN XY: 688864

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000419

Gnomad4 ASJ exome AF: 0.000755

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.00513

Gnomad4 NFE exome AF: 0.000242

Gnomad4 OTH exome AF: 0.00660

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152308 Hom.: 25 Cov.: 34 AF XY: 0.00504 AC XY: 375 AN XY: 74476

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0922

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00405 Hom.: 20

Bravo AF: 0.00417

ESP6500AA AF: 0.000759 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00481 AC: 482

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.6	H;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.78
MPC		0.59
ClinPred		0.072	T
GERP RS		5.5
Varity_R		0.82

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

LitVar

Other links and lift over

dbSNP: rs2230062; hg19: chr19-33878977; COSMIC: COSV54897502; COSMIC: COSV54897502;