chr3-51985867-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000666.3(ACY1):c.280G>A(p.Asp94Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
ACY1
NM_000666.3 missense
NM_000666.3 missense
Scores
8
9
Clinical Significance
Conservation
PhyloP100: 3.71
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3117073).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACY1 | NM_000666.3 | c.280G>A | p.Asp94Asn | missense_variant | 5/15 | ENST00000636358.2 | |
ABHD14A-ACY1 | NM_001316331.2 | c.550G>A | p.Asp184Asn | missense_variant | 7/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACY1 | ENST00000636358.2 | c.280G>A | p.Asp94Asn | missense_variant | 5/15 | 1 | NM_000666.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249988Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135198
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461296Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 726868
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74458
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 94 of the ACY1 protein (p.Asp94Asn). This variant is present in population databases (rs371375777, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ACY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1911182). 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 not expected to disrupt ACY1 protein function with a negative predictive value of 80%. 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;N;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;D;D;D;D;.;D
REVEL
Uncertain
Sift
Benign
T;.;.;.;T;T;T;T;.;T
Sift4G
Benign
T;.;.;.;T;T;T;T;.;T
Polyphen
0.076
.;.;.;B;.;.;.;B;.;.
Vest4
MVP
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ClinPred
D
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at