19-33463032-C-T

Variant names:

• chr19-33463032-C-T
• rs747700126
• NM_000285.4:c.634G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000285.4(PEPD):​c.634G>A​(p.Ala212Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: PEPD NM_000285.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 3 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: Uncertain_significance. The variant received 3 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_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31450185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4	c.634G>A	p.Ala212Thr	missense_variant	Exon 9 of 15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166057.2	c.442G>A	p.Ala148Thr	missense_variant	Exon 7 of 13		NP_001159529.1
PEPD	NM_001166056.2	c.548+15014G>A		intron_variant	Intron 7 of 12		NP_001159528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.634G>A	p.Ala212Thr	missense_variant	Exon 9 of 15	1	NM_000285.4	ENSP00000244137.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	-0.091
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;D;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.0	L;.;.
PhyloP100		3.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.93	N;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.61	T;T;.
Sift4G	Benign	0.51	T;T;.
Polyphen		0.0040	B;.;.
Vest4		0.39
MutPred		0.64		Loss of MoRF binding (P = 0.1294);.;.;
MVP		0.79
MPC		0.13
ClinPred		0.52	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs747700126; hg19: chr19-33953938;