rs74988985

Positions:

chr19-33411746-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000244137.12(PEPD):c.744T>C(p.Gly248=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,600,728 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 31 hom., cov: 33)

Exomes 𝑓: 0.017 ( 288 hom. )

Consequence

PEPD
ENST00000244137.12 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0270

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 19-33411746-A-G is Benign according to our data. Variant chr19-33411746-A-G is described in ClinVar as [Benign]. Clinvar id is 328808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-33411746-A-G is described in Lovd as [Benign]. Variant chr19-33411746-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.027 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2165/152312) while in subpopulation NFE AF= 0.0172 (1167/68018). AF 95% confidence interval is 0.0163. There are 31 homozygotes in gnomad4. There are 1183 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PEPD	NM_000285.4 linkuse as main transcript	c.744T>C	p.Gly248=	synonymous_variant	11/15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2 linkuse as main transcript	c.621T>C	p.Gly207=	synonymous_variant	9/13		NP_001159528.1
PEPD	NM_001166057.2 linkuse as main transcript	c.552T>C	p.Gly184=	synonymous_variant	9/13		NP_001159529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12 linkuse as main transcript	c.744T>C	p.Gly248=	synonymous_variant	11/15	1	NM_000285.4	ENSP00000244137	P1	P12955-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2163

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0564

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0171

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.0164

AC:

4037

AN:

246478

Hom.:

AF XY:

0.0173

AC XY:

2320

AN XY:

134050

show subpopulations

Gnomad AFR exome

AF:

0.00293

Gnomad AMR exome

AF:

0.00583

Gnomad ASJ exome

AF:

0.0275

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.0141

Gnomad FIN exome

AF:

0.0534

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0170

AC:

24618

AN:

1448416

Hom.:

288

Cov.:

AF XY:

0.0171

AC XY:

12364

AN XY:

721324

show subpopulations

Gnomad4 AFR exome

AF:

0.00244

Gnomad4 AMR exome

AF:

0.00587

Gnomad4 ASJ exome

AF:

0.0257

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0154

Gnomad4 FIN exome

AF:

0.0520

Gnomad4 NFE exome

AF:

0.0168

Gnomad4 OTH exome

AF:

0.0159

GnomAD4 genome

AF:

0.0142

AC:

2165

AN:

152312

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1183

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00313

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0126

Gnomad4 FIN

AF:

0.0564

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0102

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0144

EpiControl

AF:

0.0147

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

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

-0.60

CADD

Benign

2.5

DANN

Benign

0.40

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