19-33411746-A-G

Variant names:

• chr19-33411746-A-G
• rs74988985
• NM_000285.4:c.744T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000285.4(PEPD):​c.744T>C​(p.Gly248Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,600,728 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (31 hom., cov: 33)
  • Exomes 𝑓: 0.017 (288 hom.)
• Consequence: PEPD NM_000285.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0270
• Publications: 6 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=-0.6).
• BP6: Variant 19-33411746-A-G is Benign according to our data. Variant chr19-33411746-A-G is described in ClinVar as Benign. ClinVar VariationId is 328808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.027 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2165/152312) while in subpopulation NFE AF = 0.0172 (1167/68018). AF 95% confidence interval is 0.0163. There are 31 homozygotes in GnomAd4. There are 1183 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

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.744T>C	p.Gly248Gly	synonymous	Exon 11 of 15	NP_000276.2	A0A140VJR2
	PEPD	NM_001166056.2		c.621T>C	p.Gly207Gly	synonymous	Exon 9 of 13	NP_001159528.1	P12955-2
	PEPD	NM_001166057.2		c.552T>C	p.Gly184Gly	synonymous	Exon 9 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.744T>C	p.Gly248Gly	synonymous	Exon 11 of 15	ENSP00000244137.5	P12955-1
	PEPD	ENST00000651901.2		c.744T>C	p.Gly248Gly	synonymous	Exon 11 of 16	ENSP00000498922.2	A0A494C165
	PEPD	ENST00000588328.7	TSL:3	c.744T>C	p.Gly248Gly	synonymous	Exon 11 of 16	ENSP00000468516.4	K7ES25

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2163 AN: 152194 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0164 AC: 4037 AN: 246478 AF XY: 0.0173

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.00583

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0534

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0170 AC: 24618 AN: 1448416 Hom.: 288 Cov.: 28 AF XY: 0.0171 AC XY: 12364 AN XY: 721324

African (AFR) AF: 0.00244 AC: 81 AN: 33196

American (AMR) AF: 0.00587 AC: 262 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 668 AN: 26010

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39642

South Asian (SAS) AF: 0.0154 AC: 1325 AN: 85794

European-Finnish (FIN) AF: 0.0520 AC: 2757 AN: 52994

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5742

European-Non Finnish (NFE) AF: 0.0168 AC: 18506 AN: 1100532

Other (OTH) AF: 0.0159 AC: 952 AN: 59902

GnomAD4 genome AF: 0.0142 AC: 2165 AN: 152312 Hom.: 31 Cov.: 33 AF XY: 0.0159 AC XY: 1183 AN XY: 74476

African (AFR) AF: 0.00313 AC: 130 AN: 41568

American (AMR) AF: 0.00562 AC: 86 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4828

European-Finnish (FIN) AF: 0.0564 AC: 598 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1167 AN: 68018

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0155 Hom.: 34

Bravo AF: 0.0102

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0147

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Prolidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.5
DANN	Benign	0.40
PhyloP100		-0.027
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: rs74988985; hg19: chr19-33902652; COSMIC: COSV54896539;