19-33398094-G-A

Variant names:

• chr19-33398094-G-A
• rs889140
• NM_000285.4:c.967+3627C>T

Variant summary

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

The NM_000285.4(PEPD):​c.967+3627C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 152,112 control chromosomes in the GnomAD database, including 33,877 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 0.66 (33877 hom., cov: 33)
• Consequence: PEPD NM_000285.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 27 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000285.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEPD	NM_000285.4	MANE Select	c.967+3627C>T		intron	N/A	NP_000276.2
	PEPD	NM_001166056.2		c.844+3627C>T		intron	N/A	NP_001159528.1
	PEPD	NM_001166057.2		c.775+3627C>T		intron	N/A	NP_001159529.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEPD	ENST00000244137.12	TSL:1 MANE Select	c.967+3627C>T		intron	N/A	ENSP00000244137.5
	PEPD	ENST00000651901.2		c.967+3627C>T		intron	N/A	ENSP00000498922.2
	PEPD	ENST00000588328.7	TSL:3	c.968-1939C>T		intron	N/A	ENSP00000468516.4

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100434 AN: 151994 Hom.: 33835 Cov.: 33

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.666

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

GnomAD4 genome AF: 0.661 AC: 100537 AN: 152112 Hom.: 33877 Cov.: 33 AF XY: 0.650 AC XY: 48328 AN XY: 74366

African (AFR) AF: 0.770 AC: 31976 AN: 41522

American (AMR) AF: 0.605 AC: 9257 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2132 AN: 3470

East Asian (EAS) AF: 0.422 AC: 2160 AN: 5124

South Asian (SAS) AF: 0.358 AC: 1727 AN: 4826

European-Finnish (FIN) AF: 0.612 AC: 6488 AN: 10598

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44692 AN: 67964

Other (OTH) AF: 0.659 AC: 1391 AN: 2112

Alfa AF: 0.654 Hom.: 112061

Bravo AF: 0.674

Asia WGS AF: 0.421 AC: 1469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.43
PhyloP100		-1.2
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: rs889140; hg19: chr19-33889000; COSMIC: COSV54896662; COSMIC: COSV54896662;