19-33460220-A-G

Variant names:

• chr19-33460220-A-G
• rs2241380
• NM_000285.4:c.671+2775T>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.671+2775T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,014 control chromosomes in the GnomAD database, including 13,991 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 0.42 (13991 hom., cov: 32)
• Consequence: PEPD NM_000285.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 3 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.559 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEPD	NM_000285.4	MANE Select	c.671+2775T>C		intron	N/A	NP_000276.2	A0A140VJR2
	PEPD	NM_001166056.2		c.548+17826T>C		intron	N/A	NP_001159528.1	P12955-2
	PEPD	NM_001166057.2		c.479+2775T>C		intron	N/A	NP_001159529.1	P12955-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEPD	ENST00000244137.12	TSL:1 MANE Select	c.671+2775T>C		intron	N/A	ENSP00000244137.5	P12955-1
	PEPD	ENST00000651901.2		c.671+2775T>C		intron	N/A	ENSP00000498922.2	A0A494C165
	PEPD	ENST00000588328.7	TSL:3	c.671+2775T>C		intron	N/A	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63324 AN: 151896 Hom.: 13975 Cov.: 32

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.406

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

GnomAD4 genome AF: 0.417 AC: 63392 AN: 152014 Hom.: 13991 Cov.: 32 AF XY: 0.414 AC XY: 30733 AN XY: 74298

African (AFR) AF: 0.565 AC: 23424 AN: 41456

American (AMR) AF: 0.431 AC: 6583 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1285 AN: 3468

East Asian (EAS) AF: 0.216 AC: 1113 AN: 5158

South Asian (SAS) AF: 0.274 AC: 1324 AN: 4824

European-Finnish (FIN) AF: 0.357 AC: 3771 AN: 10558

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24589 AN: 67958

Other (OTH) AF: 0.402 AC: 848 AN: 2112

Alfa AF: 0.399 Hom.: 1638

Bravo AF: 0.434

Asia WGS AF: 0.290 AC: 1010 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.11
DANN	Benign	0.29
PhyloP100		-1.9
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: rs2241380; hg19: chr19-33951126;