chr3-51988821-C-T
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5BP4BS1_SupportingBS2
The NM_000666.3(ACY1):c.1057C>T(p.Arg353Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,196 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0036 ( 15 hom. )
Consequence
ACY1
NM_000666.3 missense
NM_000666.3 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 3.00
Genes affected
ACY1 (HGNC:177): (aminoacylase 1) This gene encodes a cytosolic, homodimeric, zinc-binding enzyme that catalyzes the hydrolysis of acylated L-amino acids to L-amino acids and an acyl group, and has been postulated to function in the catabolism and salvage of acylated amino acids. This gene is located on chromosome 3p21.1, a region reduced to homozygosity in small-cell lung cancer (SCLC), and its expression has been reported to be reduced or undetectable in SCLC cell lines and tumors. The amino acid sequence of human aminoacylase-1 is highly homologous to the porcine counterpart, and this enzyme is the first member of a new family of zinc-binding enzymes. Mutations in this gene cause aminoacylase-1 deficiency, a metabolic disorder characterized by central nervous system defects and increased urinary excretion of N-acetylated amino acids. Alternative splicing of this gene results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream ABHD14A (abhydrolase domain containing 14A) gene, as represented in GeneID:100526760. A related pseudogene has been identified on chromosome 18. [provided by RefSeq, Nov 2010]
ABHD14A-ACY1 (HGNC:38856): (ABHD14A-ACY1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring abhydrolase domain containing 14A (ABHD14A) and aminoacylase 1 (ACY1) genes on chromosome 3. The read-through transcript encodes a protein that shares sequence identity with the downstream gene product but its N-terminal region is distinct due to the use of an alternate start codon relative to the upstream gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP5
Variant 3-51988821-C-T is Pathogenic according to our data. Variant chr3-51988821-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18110.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Pathogenic=3, Likely_pathogenic=4}.
BP4
Computational evidence support a benign effect (MetaRNN=0.03669554). . Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (385/152318) while in subpopulation NFE AF= 0.00398 (271/68034). AF 95% confidence interval is 0.00359. There are 1 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 15 AR gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACY1 | ENST00000636358.2 | c.1057C>T | p.Arg353Cys | missense_variant | Exon 14 of 15 | 1 | NM_000666.3 | ENSP00000490149.1 | ||
ABHD14A-ACY1 | ENST00000463937.1 | c.1360C>T | p.Arg454Cys | missense_variant | Exon 15 of 16 | 5 | ENSP00000420487.1 |
Frequencies
GnomAD3 genomes AF: 0.00252 AC: 384AN: 152200Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00268 AC: 675AN: 251440Hom.: 4 AF XY: 0.00286 AC XY: 389AN XY: 135884
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GnomAD4 exome AF: 0.00360 AC: 5266AN: 1461878Hom.: 15 Cov.: 32 AF XY: 0.00356 AC XY: 2592AN XY: 727236
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GnomAD4 genome AF: 0.00253 AC: 385AN: 152318Hom.: 1 Cov.: 32 AF XY: 0.00259 AC XY: 193AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Aminoacylase 1 deficiency Pathogenic:5Uncertain:4
Likely pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Tarbiat Modares University | Mar 01, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 12, 2007 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 20, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Elsea Laboratory, Baylor College of Medicine | Apr 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2024 | Variant summary: ACY1 c.1057C>T (p.Arg353Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 251440 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. Due to the extremely low prevalence of this condition, this frequency does not allow conclusions about variant significance. Furthermore, the clinical/biochemical phenotype, family history or follow-up on the two homozygous individuals reported in the gnomAD database is not known. c.1057C>T has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Aminoacylase I deficiency supported by characteristic biochemical organic acid profiles (Van Coster_2005, Tylki-Szymanska_2010, Sass_2016, Smolka_2023, Kunisetty_2024). The ages of presentation were variable ranging from newborn stage to childhood for homozygous cases reports (Van Coster_2005, Tylki-Szymanska_2010, Smolka_2023, Kunisetty_2024) to a 63 year old compound heterozygous woman with dystonic symptoms starting at age 12 (Sass_2016). These data indicate that the variant is very likely to be associated with disease. However, the possibility of ACY1 deficiency having a pathogenic significance with pleiotropic clinical expression versus simply a biochemical variant phenotype has been speculated (Sass_2006). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal Aminoacylase I enzyme activity in lymphoblasts from a homozygous individual (Van Coster_2005). The following publications have been ascertained in the context of this evaluation (PMID: 26686503, 21414403, 20480396, 16274666, 38502138, 38234346). ClinVar contains an entry for this variant (Variation ID: 18110). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Nov 10, 2023 | - - |
not provided Pathogenic:2Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 09, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 07, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 353 of the ACY1 protein (p.Arg353Cys). This variant is present in population databases (rs121912698, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with aminoacylase 1 deficiency (PMID: 16274666, 16465618, 17562838, 20480396, 26686503). ClinVar contains an entry for this variant (Variation ID: 18110). 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 expected to disrupt ACY1 protein function. Experimental studies have shown that this missense change affects ACY1 function (PMID: 21414403, 26686503). 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 | Eurofins Ntd Llc (ga) | Sep 29, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | ACY1: PM3:Very Strong, PM2:Supporting, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2022 | The c.1057C>T (p.R353C) alteration is located in exon 14 (coding exon 13) of the ACY1 gene. This alteration results from a C to T substitution at nucleotide position 1057, causing the arginine (R) at amino acid position 353 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.27% (770/282836) total alleles studied, including 4 homozygotes. The highest observed frequency was 0.41% (534/129150) of European (non-Finnish) alleles. This variant has been reported in the homozygous and compound heterozygous state in several individuals with aminoacylase 1 deficiency (Van Coster, 2005; Sass, 2006; Sass, 2007; Tylki-Szymanska, 2010; Sass, 2015). In HEK293 cells, this variant demonstrated a loss of enzyme activity and no protein was detected by western blot compared to wild type (Sommer, 2011). Based on the available evidence, this alteration is classified as likely pathogenic. - |
Inborn aminoacylase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 29, 2023 | The p.Arg353Cys variant in ACY1 has been reported in at least 5 homozygous and 2 compound heterozygous individuals with aminoacylase 1 deficiency, including one homozygous individual with an additional finding of Menkes disease (Tylki-Szymanska 2010 PMID: 20480396, Sass 2007 PMID: 17562838, Sass 2006 PMID: 16465618, van Coster 2005 PMID: 16274666, Mauri 2023 PMID: 36936426). There was little consistency in the phenotypes of these individuals or in the severity of the phenotypes, aside from some neurological involvement. This variant has also been It has also been reported by other clinical laboratories in ClinVar (Variation ID 18110) and has been identified in 0.39% (271/68042) European chromosomes by gnomAD (https://gnomad.broadinstitute.org/, v3.1.2), including in 4 homozygous individuals (v2.1.1). In vitro functional studies support an impact on protein function, where HEK cells with the variant show a loss of enzyme activity and no ACY1 protein detection on a western blot compared to wildtype (Sommer 2011 PMID: 21414403), and lymphoblast cell lines generated from a homozygous patient with this variant show <1% of normal aminoacylase I enzyme activity (van Coster 2005 PMID: 16274666). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive aminoacylase 1 deficiency. ACMG/AMP criteria applied: PM3_Strong, PS3_Moderate. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;.;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;H;.;.;.;H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D;D;D;.
REVEL
Uncertain
Sift
Pathogenic
D;.;D;D;D;D;.
Sift4G
Pathogenic
D;.;D;D;D;D;.
Polyphen
1.0
.;D;.;.;.;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at