rs17569

Variant names:

• chr19-33391316-G-A
• rs17569
• NM_000285.4:c.1131C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-33391316-G-A
• chr19-33391316-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000285.4(PEPD):​c.1131C>T​(p.His377His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,610,930 control chromosomes in the GnomAD database, including 18,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1256 hom., cov: 34)
  • Exomes 𝑓: 0.15 (17039 hom.)
• Consequence: PEPD NM_000285.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.612
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-33391316-G-A is Benign according to our data. Variant chr19-33391316-G-A is described in ClinVar as Benign. ClinVar VariationId is 328799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.612 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 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.1131C>T	p.His377His	synonymous	Exon 13 of 15	NP_000276.2	A0A140VJR2
	PEPD	NM_001166056.2		c.1008C>T	p.His336His	synonymous	Exon 11 of 13	NP_001159528.1	P12955-2
	PEPD	NM_001166057.2		c.939C>T	p.His313His	synonymous	Exon 11 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.1131C>T	p.His377His	synonymous	Exon 13 of 15	ENSP00000244137.5	P12955-1
	PEPD	ENST00000651901.2		c.1131C>T	p.His377His	synonymous	Exon 13 of 16	ENSP00000498922.2	A0A494C165
	PEPD	ENST00000588328.7	TSL:3	c.1197C>T	p.His399His	synonymous	Exon 14 of 16	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16606 AN: 152082 Hom.: 1255 Cov.: 34

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.129 AC: 31540 AN: 243920 AF XY: 0.132

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.148 AC: 215804 AN: 1458730 Hom.: 17039 Cov.: 34 AF XY: 0.147 AC XY: 106752 AN XY: 725504

African (AFR) AF: 0.0222 AC: 741 AN: 33450

American (AMR) AF: 0.0751 AC: 3344 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3180 AN: 26056

East Asian (EAS) AF: 0.246 AC: 9752 AN: 39656

South Asian (SAS) AF: 0.104 AC: 8973 AN: 85898

European-Finnish (FIN) AF: 0.130 AC: 6798 AN: 52218

Middle Eastern (MID) AF: 0.122 AC: 704 AN: 5764

European-Non Finnish (NFE) AF: 0.156 AC: 173815 AN: 1110856

Other (OTH) AF: 0.141 AC: 8497 AN: 60298

GnomAD4 genome AF: 0.109 AC: 16598 AN: 152200 Hom.: 1256 Cov.: 34 AF XY: 0.106 AC XY: 7897 AN XY: 74406

African (AFR) AF: 0.0264 AC: 1098 AN: 41554

American (AMR) AF: 0.0740 AC: 1132 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 418 AN: 3472

East Asian (EAS) AF: 0.221 AC: 1140 AN: 5152

South Asian (SAS) AF: 0.0962 AC: 464 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1392 AN: 10600

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10595 AN: 67984

Other (OTH) AF: 0.111 AC: 234 AN: 2112

Alfa AF: 0.135 Hom.: 2013

Bravo AF: 0.102

Asia WGS AF: 0.149 AC: 516 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Prolidase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.0
DANN	Benign	0.74
PhyloP100		0.61
Mutation Taster		=97/3	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: rs17569; hg19: chr19-33882222; COSMIC: COSV54887682; COSMIC: COSV54887682;