NM_000285.4:c.672-10811T>C

Variant names:

• chr19-33424454-A-G
• rs4239576
• NM_000285.4:c.672-10811T>C

Variant summary

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

The NM_000285.4(PEPD):​c.672-10811T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 152,114 control chromosomes in the GnomAD database, including 11,378 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 0.37 (11378 hom., cov: 33)
• Consequence: PEPD NM_000285.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0190
• Publications: 5 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4	c.672-10811T>C		intron_variant	Intron 9 of 14	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2	c.549-10811T>C		intron_variant	Intron 7 of 12		NP_001159528.1
PEPD	NM_001166057.2	c.480-10811T>C		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.672-10811T>C		intron_variant	Intron 9 of 14	1	NM_000285.4	ENSP00000244137.5

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56708 AN: 151996 Hom.: 11357 Cov.: 33

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.338

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

GnomAD4 genome AF: 0.373 AC: 56777 AN: 152114 Hom.: 11378 Cov.: 33 AF XY: 0.372 AC XY: 27650 AN XY: 74370

African (AFR) AF: 0.523 AC: 21698 AN: 41472

American (AMR) AF: 0.353 AC: 5403 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 841 AN: 3470

East Asian (EAS) AF: 0.350 AC: 1813 AN: 5176

South Asian (SAS) AF: 0.241 AC: 1164 AN: 4828

European-Finnish (FIN) AF: 0.354 AC: 3738 AN: 10558

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21024 AN: 68004

Other (OTH) AF: 0.335 AC: 709 AN: 2116

Alfa AF: 0.315 Hom.: 12246

Bravo AF: 0.385

Asia WGS AF: 0.303 AC: 1056 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.0
DANN	Benign	0.69
PhyloP100		-0.019
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: rs4239576; hg19: chr19-33915360;