rs323893

Positions:

• chr3-51986395-C-T

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.437-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,607,980 control chromosomes in the GnomAD database, including 4,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2159 hom., cov: 32)
  • Exomes 𝑓: 0.032 (2632 hom.)
• Consequence: ACY1 NM_000666.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.33

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=-0.88).
• BP6: Variant 3-51986395-C-T is Benign according to our data. Variant chr3-51986395-C-T is described in ClinVar as [Benign]. Clinvar id is 256754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACY1	NM_000666.3	c.437-20C>T		intron_variant		ENST00000636358.2	NP_000657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACY1	ENST00000636358.2	c.437-20C>T		intron_variant		1	NM_000666.3	ENSP00000490149.1
ABHD14A-ACY1	ENST00000463937.1	c.740-20C>T		intron_variant		5		ENSP00000420487.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16259 AN: 151878 Hom.: 2135 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0524

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.0703

Gnomad SAS AF: 0.0675

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0920

GnomAD3 exomes AF: 0.0513 AC: 12145 AN: 236718 Hom.: 969 AF XY: 0.0472 AC XY: 6049 AN XY: 128158

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.0272

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.0768

Gnomad SAS exome AF: 0.0654

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0427

GnomAD4 exome AF: 0.0315 AC: 45875 AN: 1455984 Hom.: 2632 Cov.: 33 AF XY: 0.0315 AC XY: 22773 AN XY: 723778

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0270

Gnomad4 EAS exome AF: 0.0742

Gnomad4 SAS exome AF: 0.0627

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0504

GnomAD4 genome AF: 0.107 AC: 16331 AN: 151996 Hom.: 2159 Cov.: 32 AF XY: 0.105 AC XY: 7812 AN XY: 74312

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.0523

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.0699

Gnomad4 SAS AF: 0.0673

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0934

Alfa AF: 0.0662 Hom.: 251

Bravo AF: 0.122

Asia WGS AF: 0.110 AC: 384 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

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	-0.88
CADD	Benign	0.023
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs323893; hg19: chr3-52020411; COSMIC: COSV68344565; COSMIC: COSV68344565;