Genetic Variant PPT2:p.Ala99Ser (chr6-32155141-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005155.7(PPT2):c.295G>T(p.Ala99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPT2
NM_005155.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.41

Variant links:

Genes affected

PPT2 (HGNC:9326): (palmitoyl-protein thioesterase 2) This gene encodes a member of the palmitoyl-protein thioesterase family. The encoded glycosylated lysosomal protein has palmitoyl-CoA hydrolase activity in vitro, but does not hydrolyze palmitate from cysteine residues in proteins. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream EGFL8 (EGF-like-domain, multiple 8) gene. [provided by RefSeq, Feb 2011]

PPT2 links:

PPT2-EGFL8 (HGNC:48343): (PPT2-EGFL8 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring PPT2 (palmitoyl-protein thioesterase 2) and EGFL8 (EGF-like-domain, multiple 8) genes located in the major histocompatibility complex class III region of chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

PPT2-EGFL8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1259476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT2	NM_005155.7 link	c.295G>T	p.Ala99Ser	missense_variant	Exon 3 of 9	ENST00000324816.11	NP_005146.4	Q9UMR5-1A0A1U9X8D2
PPT2	NM_138717.3 link	c.313G>T	p.Ala105Ser	missense_variant	Exon 3 of 9		NP_619731.2	Q9UMR5-3
PPT2	NM_001204103.2 link	c.295G>T	p.Ala99Ser	missense_variant	Exon 3 of 9		NP_001191032.1	Q9UMR5-1A0A1U9X8D2
PPT2-EGFL8	NR_037861.1 link	n.709G>T		non_coding_transcript_exon_variant	Exon 3 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT2	ENST00000324816.11 link	c.295G>T	p.Ala99Ser	missense_variant	Exon 3 of 9	1	NM_005155.7	ENSP00000320528.6		Q9UMR5-1
PPT2-EGFL8	ENST00000422437.5 link	n.295G>T		non_coding_transcript_exon_variant	Exon 3 of 21	5		ENSP00000457534.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246618

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134394

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460830

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726722

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.061

T;.;T;T;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.89

D;D;.;D;.;.

M_CAP

Benign

0.036

MetaRNN

Benign

0.13

T;T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.85

.;.;L;L;L;L

PrimateAI

Benign

0.40

PROVEAN

Benign

0.53

N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.63

T;T;T;T;T;T

Sift4G

Benign

0.54

T;T;T;T;T;T

Polyphen

0.0040

.;.;B;B;B;B

Vest4

0.15, 0.15, 0.14

MutPred

0.35

Gain of methylation at K100 (P = 0.0743);.;Gain of methylation at K100 (P = 0.0743);Gain of methylation at K100 (P = 0.0743);Gain of methylation at K100 (P = 0.0743);Gain of methylation at K100 (P = 0.0743);

MVP

0.36

MPC

0.71

ClinPred

0.28

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over