PEPD p.Gly448Arg

Variant names:

• chr19-33387892-C-G
• NM_000285.4:c.1342G>C
• PEPD p.Gly448Arg

Your query was ambiguous. Multiple possible variants found:

• chr19-33387892-C-G
• chr19-33387892-C-T
• chr19-33387890-CCC-ACG
• chr19-33387890-CCC-GCG
• chr19-33387890-CCC-TCG
• chr19-33387890-CCC-TCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000285.4(PEPD):​c.1342G>C​(p.Gly448Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PEPD NM_000285.4 missense, splice_region
• Scores: Splicing: ADA: 0.9014
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 0 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, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

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.1342G>C	p.Gly448Arg	missense splice_region	Exon 14 of 15	NP_000276.2	A0A140VJR2
	PEPD	NM_001166056.2		c.1219G>C	p.Gly407Arg	missense splice_region	Exon 12 of 13	NP_001159528.1	P12955-2
	PEPD	NM_001166057.2		c.1150G>C	p.Gly384Arg	missense splice_region	Exon 12 of 13	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.1342G>C	p.Gly448Arg	missense splice_region	Exon 14 of 15	ENSP00000244137.5	P12955-1
	PEPD	ENST00000651901.2		c.1342G>C	p.Gly448Arg	missense splice_region	Exon 14 of 16	ENSP00000498922.2	A0A494C165
	PEPD	ENST00000588328.7	TSL:3	c.1408G>C	p.Gly470Arg	missense splice_region	Exon 15 of 16	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		5.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.99
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.71
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-33878798;