19-33387304-A-T

Position:

chr19-33387304-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_000285.4(PEPD):c.*40T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,611,578 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

PEPD
NM_000285.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.636

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00107 (163/152310) while in subpopulation AFR AF= 0.00359 (149/41558). AF 95% confidence interval is 0.00312. There are 1 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
PEPD	NM_000285.4 linkuse as main transcript	c.*40T>A	3_prime_UTR_variant	15/15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2 linkuse as main transcript	c.*40T>A	3_prime_UTR_variant	13/13		NP_001159528.1
PEPD	NM_001166057.2 linkuse as main transcript	c.*40T>A	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 linkuse as main transcript	c.*40T>A		3_prime_UTR_variant	15/15	1	NM_000285.4	ENSP00000244137	P1	P12955-1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000245

AC:

AN:

248604

Hom.:

AF XY:

0.000200

AC XY:

AN XY:

134980

show subpopulations

Gnomad AFR exome

AF:

0.00356

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000994

AC:

145

AN:

1459268

Hom.:

Cov.:

AF XY:

0.0000813

AC XY:

AN XY:

725672

show subpopulations

Gnomad4 AFR exome

AF:

0.00383

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152310

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00359

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.00114

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Prolidase deficiency

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.49

DANN

Benign

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over