NM_000285.4:c.*211T>C

Variant names:

• chr19-33387133-A-G
• rs3556
• NM_000285.4:c.*211T>C

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.*211T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 600,984 control chromosomes in the GnomAD database, including 21,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7831 hom., cov: 33)
  • Exomes 𝑓: 0.24 (13721 hom.)
• Consequence: PEPD NM_000285.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.508
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-33387133-A-G is Benign according to our data. Variant chr19-33387133-A-G is described in ClinVar as Benign. ClinVar VariationId is 328777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 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.*211T>C		3_prime_UTR	Exon 15 of 15	NP_000276.2	A0A140VJR2
	PEPD	NM_001166056.2		c.*211T>C		3_prime_UTR	Exon 13 of 13	NP_001159528.1	P12955-2
	PEPD	NM_001166057.2		c.*211T>C		3_prime_UTR	Exon 13 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.*211T>C		3_prime_UTR	Exon 15 of 15	ENSP00000244137.5	P12955-1
	PEPD	ENST00000651901.2		c.*211T>C		3_prime_UTR	Exon 16 of 16	ENSP00000498922.2	A0A494C165
	PEPD	ENST00000588328.7	TSL:3	c.*211T>C		3_prime_UTR	Exon 16 of 16	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46075 AN: 151900 Hom.: 7817 Cov.: 33

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.240 AC: 107911 AN: 448966 Hom.: 13721 Cov.: 4 AF XY: 0.235 AC XY: 55356 AN XY: 235520

African (AFR) AF: 0.472 AC: 5869 AN: 12440

American (AMR) AF: 0.193 AC: 3583 AN: 18570

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 3854 AN: 13674

East Asian (EAS) AF: 0.168 AC: 5174 AN: 30846

South Asian (SAS) AF: 0.156 AC: 7048 AN: 45250

European-Finnish (FIN) AF: 0.239 AC: 6995 AN: 29308

Middle Eastern (MID) AF: 0.224 AC: 440 AN: 1962

European-Non Finnish (NFE) AF: 0.252 AC: 68359 AN: 270982

Other (OTH) AF: 0.254 AC: 6589 AN: 25934

GnomAD4 genome AF: 0.303 AC: 46123 AN: 152018 Hom.: 7831 Cov.: 33 AF XY: 0.298 AC XY: 22136 AN XY: 74274

African (AFR) AF: 0.467 AC: 19359 AN: 41470

American (AMR) AF: 0.212 AC: 3233 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 985 AN: 3470

East Asian (EAS) AF: 0.196 AC: 1013 AN: 5168

South Asian (SAS) AF: 0.156 AC: 750 AN: 4818

European-Finnish (FIN) AF: 0.254 AC: 2687 AN: 10574

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.255 AC: 17306 AN: 67950

Other (OTH) AF: 0.271 AC: 573 AN: 2112

Alfa AF: 0.266 Hom.: 10104

Bravo AF: 0.311

Asia WGS AF: 0.195 AC: 681 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.71
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3556; hg19: chr19-33878039;