3-49682366-C-T

Position:

• chr3-49682366-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0015 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (19 hom.)
• Consequence: APEH NM_001640.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APEH	NM_001640.4	c.1622C>T	p.Thr541Met	missense_variant	18/22	ENST00000296456.10	NP_001631.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APEH	ENST00000296456.10	c.1622C>T	p.Thr541Met	missense_variant	18/22	1	NM_001640.4	ENSP00000296456.5
APEH	ENST00000438011.5	c.1622C>T	p.Thr541Met	missense_variant	18/22	1		ENSP00000415862.1
APEH	ENST00000469362.6	n.*322C>T		non_coding_transcript_exon_variant	7/9	3		ENSP00000438180.1
APEH	ENST00000469362.6	n.*322C>T		3_prime_UTR_variant	7/9	3		ENSP00000438180.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152222 Hom.: 6 Cov.: 33

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

GnomAD3 exomes AF: 0.00338 AC: 844 AN: 249972 Hom.: 17 AF XY: 0.00322 AC XY: 435 AN XY: 135224

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 SAS exome AF: 0.00128

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.: 19 Cov.: 34 AF XY: 0.00121 AC XY: 878 AN XY: 726922

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152340 Hom.: 6 Cov.: 33 AF XY: 0.00157 AC XY: 117 AN XY: 74498

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0347

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00132 Hom.: 8

Bravo AF: 0.00161

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00325 AC: 395

Asia WGS AF: 0.0120 AC: 42 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	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.41	N
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.56	T
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	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
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

Other links and lift over

dbSNP: rs3816877; hg19: chr3-49719799; COSMIC: COSV56535874; COSMIC: COSV56535874;