rs121917724

Variant names:

• chr19-33387892-C-T
• rs121917724
• NM_000285.4:c.1342G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000285.4(PEPD):​c.1342G>A​(p.Gly448Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000364 in 1,564,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000711771: "In addition, in vitro functional studies provide some evidence that the p.Gly448Arg variant may impact protein function (Ledoux 1996, Besio 2013)."" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PEPD NM_000285.4 missense, splice_region
• Scores: Splicing: ADA: 0.8907
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.67
• Publications: 15 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000711771: "In addition, in vitro functional studies provide some evidence that the p.Gly448Arg variant may impact protein function (Ledoux 1996, Besio 2013)."; SCV000914837: "Ledoux et al. (1994), Lupi et al. (2006) and Besio et al. (2013) demonstrated that prolidase activity in fibroblasts from patients with PD with the p.Gly448Arg variant was reduced to <2% to 13.1% when compared to controls. In addition, transient expression of the p.Gly448Arg variant in COS1 cells produced an inactive enzyme (Ledoux et al. 1996), and a recombinant PEPD enzyme containing the p.Gly448Arg variant showed very low catalytic efficiency, thermal instability, and changes in protein conformations (Besio et al. 2013)."; SCV001445902: Studies using patient fibroblast lines and recombinant prolidase demonstrated that this variant leads to decreased catalytic efficiency, thermal stability and cofactor binding (PMID: 23516557). Additionally, an in vitro experiment in COS-1 cells demonstrated that this variant reduces prolidase activity to undetectable levels (PMID: 8900231).; SCV003450616: Experimental studies have shown that this missense change affects PEPD function (PMID: 8900231, 23516557).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-33387892-C-T is Pathogenic according to our data. Variant chr19-33387892-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000179 AC: 3 AN: 167316 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000300

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 51 AN: 1411860 Hom.: 0 Cov.: 31 AF XY: 0.0000444 AC XY: 31 AN XY: 697646

African (AFR) AF: 0.00 AC: 0 AN: 32370

American (AMR) AF: 0.00 AC: 0 AN: 37418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 37206

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5056

European-Non Finnish (NFE) AF: 0.0000432 AC: 47 AN: 1086888

Other (OTH) AF: 0.0000513 AC: 3 AN: 58488

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000171 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Prolidase deficiency (6)
1	-	-	not provided (1)

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	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.29	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
Polyphen		1.0	D
Vest4		1.0
MutPred		0.99		Gain of MoRF binding (P = 0.0178)
MVP		0.97
MPC		0.58
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.99
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Pathogenic	0.74
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: rs121917724; hg19: chr19-33878798;