rs747700126

chr19-33463032-C-Achr19-33463032-C-Gchr19-33463032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000285.4(PEPD):c.634G>T(p.Ala212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,433,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A212P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PEPD NM_000285.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-33463032-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209997.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25659776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEPD	NM_000285.4	c.634G>T	p.Ala212Ser	missense_variant	9/15	ENST00000244137.12
PEPD	NM_001166057.2	c.442G>T	p.Ala148Ser	missense_variant	7/13
PEPD	NM_001166056.2	c.548+15014G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEPD	ENST00000244137.12	c.634G>T	p.Ala212Ser	missense_variant	9/15	1	NM_000285.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249576 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135404

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 SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1433940 Hom.: 0 Cov.: 27 AF XY: 0.00000280 AC XY: 2 AN XY: 715194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.88
DEOGEN2	Benign	0.20	T;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.0043
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.31	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.19	N;N;.
REVEL	Benign	0.25
Sift	Benign	0.74	T;T;.
Sift4G	Benign	0.57	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.36
MutPred		0.61		Gain of disorder (P = 0.0227);.;.;
MVP		0.76
MPC		0.11
ClinPred		0.45	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747700126; hg19: chr19-33953938;