ACY1 p.Glu233Asp

Variant names:

• chr3-51987188-A-T
• NM_000666.3:c.699A>T
• ACY1 p.Glu233Asp

Your query was ambiguous. Multiple possible variants found:

• chr3-51987188-A-T
• chr3-51987188-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1_Moderate PM2

The NM_000666.3(ACY1):​c.699A>T​(p.Glu233Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACY1 NM_000666.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_000666.3 (ACY1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000666.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACY1	NM_000666.3	MANE Select	c.699A>T	p.Glu233Asp	missense	Exon 10 of 15	NP_000657.1	Q03154-1
	ABHD14A-ACY1	NM_001316331.2		c.969A>T	p.Glu323Asp	missense	Exon 12 of 17	NP_001303260.1
	ACY1	NM_001198895.2		c.699A>T	p.Glu233Asp	missense	Exon 10 of 15	NP_001185824.1	Q03154-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACY1	ENST00000636358.2	TSL:1 MANE Select	c.699A>T	p.Glu233Asp	missense	Exon 10 of 15	ENSP00000490149.1	Q03154-1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.1002A>T	p.Glu334Asp	missense	Exon 11 of 16	ENSP00000420487.1	C9JMV9
	ACY1	ENST00000404366.7	TSL:1	c.699A>T	p.Glu233Asp	missense	Exon 10 of 15	ENSP00000384296.2	Q03154-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.013	D
PromoterAI		0.026	Neutral
Varity_R		0.82
gMVP		0.81
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-52021204;