rs780954540

chr2-44326771-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001171613.2(PREPL):c.1420G>A(p.Val474Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.95

Genes affected

PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2	c.1420G>A	p.Val474Met	missense_variant	10/14	ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.1420G>A	p.Val474Met	missense_variant	10/14	1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251374 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135850

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: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727240

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: 0.000104

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 563 of the PREPL protein (p.Val563Met). This variant is present in population databases (rs780954540, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PREPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 548500). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PREPL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.1687G>A (p.V563M) alteration is located in exon 10 (coding exon 10) of the PREPL gene. This alteration results from a G to A substitution at nucleotide position 1687, causing the valine (V) at amino acid position 563 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Benign	0.10
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;.;.;.;.;.;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.13	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.82, 1.0	.;.;.;D;D;D;D;P;D
Vest4		0.66
MutPred		0.56		.;.;.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;.;
MVP		0.26
MPC		0.023
ClinPred		0.36	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs780954540; hg19: chr2-44553910;