Genetic Variant APEH:p.Thr541Met (chr3-49682366-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001640.4(APEH):c.1622C>T(p.Thr541Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,666 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0015 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 19 hom. )

Consequence

APEH
NM_001640.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

Publications

16 publications found

Variant links:

Genes affected

APEH (HGNC:586): (acylaminoacyl-peptide hydrolase) This gene encodes the enzyme acylpeptide hydrolase, which catalyzes the hydrolysis of the terminal acetylated amino acid preferentially from small acetylated peptides. The acetyl amino acid formed by this hydrolase is further processed to acetate and a free amino acid by an aminoacylase. This gene is located within the same region of chromosome 3 (3p21) as the aminoacylase gene, and deletions at this locus are also associated with a decrease in aminoacylase activity. The acylpeptide hydrolase is a homotetrameric protein of 300 kDa with each subunit consisting of 732 amino acid residues. It can play an important role in destroying oxidatively damaged proteins in living cells. Deletions of this gene locus are found in various types of carcinomas, including small cell lung carcinoma and renal cell carcinoma. [provided by RefSeq, Jul 2008]

APEH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011851877).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00151 (230/152340) while in subpopulation EAS AF = 0.0347 (180/5180). AF 95% confidence interval is 0.0306. There are 6 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEH	NM_001640.4 link	c.1622C>T	p.Thr541Met	missense_variant	Exon 18 of 22	ENST00000296456.10	NP_001631.3	P13798

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEH	ENST00000296456.10 link	c.1622C>T	p.Thr541Met	missense_variant	Exon 18 of 22	1	NM_001640.4	ENSP00000296456.5		P13798

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

231

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0349

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00338

AC:

844

AN:

249972

AF XY:

0.00322

show subpopulations

Gnomad AFR exome

AF:

0.000495

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0413

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.000984

GnomAD4 exome

AF:

0.00121

AC:

1761

AN:

1461326

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

878

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33472

American (AMR)

AF:

0.000134

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0312

AC:

1240

AN:

39682

South Asian (SAS)

AF:

0.00101

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000276

AC:

307

AN:

1111746

Other (OTH)

AF:

0.00186

AC:

112

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00151

AC:

230

AN:

152340

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41576

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0347

AC:

180

AN:

5180

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.00161

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00325

AC:

395

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.41

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

1.9

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.63

N;N

REVEL

Benign

0.13

Sift

Benign

0.13

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.95

P;D

Vest4

0.33

MVP

0.77

MPC

0.69

ClinPred

0.022

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.39

Mutation Taster

=89/11

polymorphism

(source)

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

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3-49682366-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over