rs323894

Positions:

• chr3-51987076-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000666.3(ACY1):​c.657+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,613,974 control chromosomes in the GnomAD database, including 3,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (1511 hom., cov: 33)
  • Exomes 𝑓: 0.023 (1787 hom.)
• Consequence: ACY1 NM_000666.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0400

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]

ACY1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-51987076-A-G is Benign according to our data. Variant chr3-51987076-A-G is described in ClinVar as [Benign]. Clinvar id is 256756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACY1	NM_000666.3	c.657+15A>G		intron_variant		ENST00000636358.2	NP_000657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACY1	ENST00000636358.2	c.657+15A>G		intron_variant		1	NM_000666.3	ENSP00000490149.1
ABHD14A-ACY1	ENST00000463937.1	c.960+15A>G		intron_variant		5		ENSP00000420487.1

Frequencies

GnomAD3 genomes AF: 0.0873 AC: 13280 AN: 152098 Hom.: 1488 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0761

GnomAD3 exomes AF: 0.0400 AC: 10053 AN: 251432 Hom.: 738 AF XY: 0.0358 AC XY: 4863 AN XY: 135904

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.0770

Gnomad SAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0322

GnomAD4 exome AF: 0.0226 AC: 33093 AN: 1461758 Hom.: 1787 Cov.: 32 AF XY: 0.0223 AC XY: 16186 AN XY: 727186

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.0240

Gnomad4 ASJ exome AF: 0.0225

Gnomad4 EAS exome AF: 0.0746

Gnomad4 SAS exome AF: 0.0363

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0401

GnomAD4 genome AF: 0.0877 AC: 13352 AN: 152216 Hom.: 1511 Cov.: 33 AF XY: 0.0858 AC XY: 6390 AN XY: 74434

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.0398

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.0716

Gnomad4 SAS AF: 0.0398

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0777

Alfa AF: 0.0503 Hom.: 137

Bravo AF: 0.0993

Asia WGS AF: 0.0940 AC: 329 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.8
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs323894; hg19: chr3-52021092; COSMIC: COSV68343661; COSMIC: COSV68343661;