NM_000666.3:c.527-17C>A

Variant names:

• chr3-51986588-C-A
• rs887541
• NM_000666.3:c.527-17C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000666.3(ACY1):​c.527-17C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,614,130 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (175 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (169 hom.)
• Consequence: ACY1 NM_000666.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00300
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 3-51986588-C-A is Benign according to our data. Variant chr3-51986588-C-A is described in ClinVar as Benign. ClinVar VariationId is 256755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0858 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACY1	NM_000666.3	MANE Select	c.527-17C>A		intron	N/A	NP_000657.1
	ABHD14A-ACY1	NM_001316331.2		c.797-17C>A		intron	N/A	NP_001303260.1
	ACY1	NM_001198895.2		c.527-17C>A		intron	N/A	NP_001185824.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACY1	ENST00000636358.2	TSL:1 MANE Select	c.527-17C>A		intron	N/A	ENSP00000490149.1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.830-17C>A		intron	N/A	ENSP00000420487.1
	ACY1	ENST00000404366.7	TSL:1	c.527-17C>A		intron	N/A	ENSP00000384296.2

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3964 AN: 152172 Hom.: 172 Cov.: 33

Gnomad AFR AF: 0.0879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00741 AC: 1864 AN: 251434 AF XY: 0.00558

Gnomad AFR exome AF: 0.0905

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00323 AC: 4727 AN: 1461840 Hom.: 169 Cov.: 33 AF XY: 0.00290 AC XY: 2110 AN XY: 727226

African (AFR) AF: 0.0885 AC: 2961 AN: 33472

American (AMR) AF: 0.00796 AC: 356 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.000703 AC: 782 AN: 1111988

Other (OTH) AF: 0.00816 AC: 493 AN: 60396

GnomAD4 genome AF: 0.0262 AC: 3986 AN: 152290 Hom.: 175 Cov.: 33 AF XY: 0.0245 AC XY: 1828 AN XY: 74468

African (AFR) AF: 0.0882 AC: 3665 AN: 41542

American (AMR) AF: 0.0137 AC: 210 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68024

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0145 Hom.: 26

Bravo AF: 0.0299

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		-0.0030
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs887541; hg19: chr3-52020604;