rs369887158

Variant names:

• chr2-44323381-T-A
• rs369887158
• NM_001171613.2:c.1510A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001171613.2(PREPL):​c.1510A>T​(p.Met504Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,603,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M504I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0350
• Publications: 0 publications found

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]

PREPL Gene-Disease associations (from GenCC):

• hypotonia-cystinuria syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• myasthenic syndrome, congenital, 22

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04466787).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171613.2. 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
	PREPL	NM_001171613.2	MANE Select	c.1510A>T	p.Met504Leu	missense	Exon 11 of 14	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.1777A>T	p.Met593Leu	missense	Exon 12 of 15	NP_001165074.1	Q4J6C6-1
	PREPL	NM_001171606.2		c.1777A>T	p.Met593Leu	missense	Exon 12 of 15	NP_001165077.1	Q4J6C6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000409411.6	TSL:1 MANE Select	c.1510A>T	p.Met504Leu	missense	Exon 11 of 14	ENSP00000387095.2	Q4J6C6-4
	PREPL	ENST00000260648.10	TSL:1	c.1777A>T	p.Met593Leu	missense	Exon 11 of 14	ENSP00000260648.6	Q4J6C6-1
	PREPL	ENST00000409936.5	TSL:1	c.1777A>T	p.Met593Leu	missense	Exon 12 of 15	ENSP00000386543.1	Q4J6C6-1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000489 AC: 12 AN: 245592 AF XY: 0.0000528

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000982

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000198 AC: 287 AN: 1451964 Hom.: 0 Cov.: 31 AF XY: 0.000195 AC XY: 141 AN XY: 722424

African (AFR) AF: 0.00 AC: 0 AN: 33078

American (AMR) AF: 0.0000229 AC: 1 AN: 43584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 84586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000245 AC: 271 AN: 1106140

Other (OTH) AF: 0.000250 AC: 15 AN: 60062

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Myasthenic syndrome, congenital, 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.035
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.025
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.44		Gain of helix (P = 0.0854)
MVP		0.14
MPC		0.0051
ClinPred		0.035	T
GERP RS		1.7
PromoterAI		-0.0088	Neutral
Varity_R		0.027
gMVP		0.45
Mutation Taster		=96/4	polymorphism

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: rs369887158; hg19: chr2-44550520;