19-33387133-A-G

Position:

• chr19-33387133-A-G

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.*211T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 600,984 control chromosomes in the GnomAD database, including 21,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7831 hom., cov: 33)
  • Exomes 𝑓: 0.24 (13721 hom.)
• Consequence: PEPD NM_000285.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.508

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 (BayesDel_noAF=-0.84).
• BP6: Variant 19-33387133-A-G is Benign according to our data. Variant chr19-33387133-A-G is described in ClinVar as [Benign]. Clinvar id is 328777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEPD	NM_000285.4	c.*211T>C		3_prime_UTR_variant	15/15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2	c.*211T>C		3_prime_UTR_variant	13/13		NP_001159528.1
PEPD	NM_001166057.2	c.*211T>C		3_prime_UTR_variant	13/13		NP_001159529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.*211T>C		3_prime_UTR_variant	15/15	1	NM_000285.4	ENSP00000244137	P1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46075 AN: 151900 Hom.: 7817 Cov.: 33

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.240 AC: 107911 AN: 448966 Hom.: 13721 Cov.: 4 AF XY: 0.235 AC XY: 55356 AN XY: 235520

Gnomad4 AFR exome AF: 0.472

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.254

GnomAD4 genome AF: 0.303 AC: 46123 AN: 152018 Hom.: 7831 Cov.: 33 AF XY: 0.298 AC XY: 22136 AN XY: 74274

Gnomad4 AFR AF: 0.467

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.271

Alfa AF: 0.260 Hom.: 5988

Bravo AF: 0.311

Asia WGS AF: 0.195 AC: 681 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3556; hg19: chr19-33878039;