19-33441409-T-C

Variant names:

• chr19-33441409-T-C
• rs7248389
• NM_000285.4:c.671+21586A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000285.4(PEPD):​c.671+21586A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 152,016 control chromosomes in the GnomAD database, including 24,568 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24568 hom., cov: 32)
• Consequence: PEPD NM_000285.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.444
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• prolidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4	c.671+21586A>G		intron_variant	Intron 9 of 14	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2	c.549-27766A>G		intron_variant	Intron 7 of 12		NP_001159528.1
PEPD	NM_001166057.2	c.479+21586A>G		intron_variant	Intron 7 of 12		NP_001159529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.671+21586A>G		intron_variant	Intron 9 of 14	1	NM_000285.4	ENSP00000244137.5

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85206 AN: 151898 Hom.: 24534 Cov.: 32

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.534

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.561 AC: 85282 AN: 152016 Hom.: 24568 Cov.: 32 AF XY: 0.552 AC XY: 40984 AN XY: 74294

African (AFR) AF: 0.651 AC: 26997 AN: 41472

American (AMR) AF: 0.406 AC: 6204 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1789 AN: 3470

East Asian (EAS) AF: 0.421 AC: 2167 AN: 5144

South Asian (SAS) AF: 0.407 AC: 1957 AN: 4808

European-Finnish (FIN) AF: 0.482 AC: 5094 AN: 10566

Middle Eastern (MID) AF: 0.524 AC: 153 AN: 292

European-Non Finnish (NFE) AF: 0.579 AC: 39373 AN: 67960

Other (OTH) AF: 0.528 AC: 1117 AN: 2114

Alfa AF: 0.569 Hom.: 75409

Bravo AF: 0.562

Asia WGS AF: 0.423 AC: 1475 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	11
DANN	Benign	0.38
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7248389; hg19: chr19-33932315; COSMIC: COSV54897134;