rs17570

Variant names:

• chr19-33387931-G-A
• rs17570
• NM_000285.4:c.1303C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-33387931-G-A
• chr19-33387931-G-C
• chr19-33387931-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000285.4(PEPD):​c.1303C>T​(p.Leu435Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,594,290 control chromosomes in the GnomAD database, including 55,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L435L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7715 hom., cov: 34)
  • Exomes 𝑓: 0.25 (47495 hom.)
• Consequence: PEPD NM_000285.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.70
• Publications: 45 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.922087E-4).
• BP6: Variant 19-33387931-G-A is Benign according to our data. Variant chr19-33387931-G-A is described in ClinVar as Benign. ClinVar VariationId is 328791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEPD	NM_000285.4	MANE Select	c.1303C>T	p.Leu435Phe	missense	Exon 14 of 15	NP_000276.2
	PEPD	NM_001166056.2		c.1180C>T	p.Leu394Phe	missense	Exon 12 of 13	NP_001159528.1
	PEPD	NM_001166057.2		c.1111C>T	p.Leu371Phe	missense	Exon 12 of 13	NP_001159529.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEPD	ENST00000244137.12	TSL:1 MANE Select	c.1303C>T	p.Leu435Phe	missense	Exon 14 of 15	ENSP00000244137.5
	PEPD	ENST00000651901.2		c.1303C>T	p.Leu435Phe	missense	Exon 14 of 16	ENSP00000498922.2
	PEPD	ENST00000588328.7	TSL:3	c.1369C>T	p.Leu457Phe	missense	Exon 15 of 16	ENSP00000468516.4

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45870 AN: 152108 Hom.: 7707 Cov.: 34

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.229 AC: 48307 AN: 211038 AF XY: 0.225

Gnomad AFR exome AF: 0.457

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.188

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.252 AC: 362971 AN: 1442064 Hom.: 47495 Cov.: 34 AF XY: 0.248 AC XY: 177537 AN XY: 715260

African (AFR) AF: 0.482 AC: 16010 AN: 33232

American (AMR) AF: 0.173 AC: 7262 AN: 41948

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7284 AN: 25766

East Asian (EAS) AF: 0.172 AC: 6709 AN: 38948

South Asian (SAS) AF: 0.153 AC: 12740 AN: 83284

European-Finnish (FIN) AF: 0.242 AC: 12273 AN: 50646

Middle Eastern (MID) AF: 0.246 AC: 1407 AN: 5708

European-Non Finnish (NFE) AF: 0.258 AC: 284377 AN: 1102920

Other (OTH) AF: 0.250 AC: 14909 AN: 59612

GnomAD4 genome AF: 0.302 AC: 45911 AN: 152226 Hom.: 7715 Cov.: 34 AF XY: 0.296 AC XY: 22024 AN XY: 74422

African (AFR) AF: 0.461 AC: 19163 AN: 41532

American (AMR) AF: 0.210 AC: 3211 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 987 AN: 3470

East Asian (EAS) AF: 0.196 AC: 1010 AN: 5158

South Asian (SAS) AF: 0.154 AC: 741 AN: 4826

European-Finnish (FIN) AF: 0.254 AC: 2692 AN: 10602

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17320 AN: 68010

Other (OTH) AF: 0.270 AC: 570 AN: 2114

Alfa AF: 0.260 Hom.: 10977

Bravo AF: 0.309

TwinsUK AF: 0.262 AC: 971

ALSPAC AF: 0.254 AC: 980

ESP6500AA AF: 0.397 AC: 1543

ESP6500EA AF: 0.240 AC: 1977

ExAC AF: 0.213 AC: 25299

Asia WGS AF: 0.192 AC: 670 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Prolidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.35
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.079	T
MetaRNN	Benign	0.00099	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.96	L
PhyloP100		2.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Benign	0.84	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.046
MPC		0.12
ClinPred		0.011	T
GERP RS		3.4
Varity_R		0.27
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17570; hg19: chr19-33878837; COSMIC: COSV54890582; COSMIC: COSV54890582;