NM_000666.3:c.657+15A>G

Variant names:

• chr3-51987076-A-G
• rs323894
• NM_000666.3:c.657+15A>G

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.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
• Publications: 4 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=-0.83).
• BP6: Variant 3-51987076-A-G is Benign according to our data. Variant chr3-51987076-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.657+15A>G		intron	N/A	NP_000657.1
	ABHD14A-ACY1	NM_001316331.2		c.927+15A>G		intron	N/A	NP_001303260.1
	ACY1	NM_001198895.2		c.657+15A>G		intron	N/A	NP_001185824.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACY1	ENST00000636358.2	TSL:1 MANE Select	c.657+15A>G		intron	N/A	ENSP00000490149.1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.960+15A>G		intron	N/A	ENSP00000420487.1
	ACY1	ENST00000404366.7	TSL:1	c.657+15A>G		intron	N/A	ENSP00000384296.2

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

GnomAD2 exomes AF: 0.0400 AC: 10053 AN: 251432 AF XY: 0.0358

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 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

African (AFR) AF: 0.270 AC: 9033 AN: 33472

American (AMR) AF: 0.0240 AC: 1074 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 587 AN: 26136

East Asian (EAS) AF: 0.0746 AC: 2962 AN: 39700

South Asian (SAS) AF: 0.0363 AC: 3131 AN: 86256

European-Finnish (FIN) AF: 0.0182 AC: 970 AN: 53350

Middle Eastern (MID) AF: 0.0718 AC: 411 AN: 5724

European-Non Finnish (NFE) AF: 0.0112 AC: 12502 AN: 1112002

Other (OTH) AF: 0.0401 AC: 2423 AN: 60394

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

African (AFR) AF: 0.261 AC: 10844 AN: 41498

American (AMR) AF: 0.0398 AC: 609 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.0716 AC: 371 AN: 5178

South Asian (SAS) AF: 0.0398 AC: 192 AN: 4828

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10626

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 920 AN: 67996

Other (OTH) AF: 0.0777 AC: 164 AN: 2110

Alfa AF: 0.0503 Hom.: 137

Bravo AF: 0.0993

Asia WGS AF: 0.0940 AC: 329 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	-0.83
CADD	Benign	4.8
DANN	Benign	0.77
PhyloP100		-0.040
PromoterAI		-0.0075	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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