rs2229152

Variant names:

• chr3-51989004-C-T
• rs2229152
• NM_000666.3:c.1156C>T
• ACY1 p.Arg386Cys

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000666.3(ACY1):​c.1156C>T​(p.Arg386Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,614,126 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (6 hom.)
• Consequence: ACY1 NM_000666.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.95
• Publications: 13 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012215853).
• BP6: Variant 3-51989004-C-T is Benign according to our data. Variant chr3-51989004-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 712435.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00495 (753/152264) while in subpopulation AFR AF = 0.0164 (683/41544). AF 95% confidence interval is 0.0154. There are 6 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1156C>T	p.Arg386Cys	missense	Exon 15 of 15	NP_000657.1	Q03154-1
	ABHD14A-ACY1	NM_001316331.2		c.1426C>T	p.Arg476Cys	missense	Exon 17 of 17	NP_001303260.1
	ACY1	NM_001198895.2		c.1156C>T	p.Arg386Cys	missense	Exon 15 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.1156C>T	p.Arg386Cys	missense	Exon 15 of 15	ENSP00000490149.1	Q03154-1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.1459C>T	p.Arg487Cys	missense	Exon 16 of 16	ENSP00000420487.1	C9JMV9
	ACY1	ENST00000404366.7	TSL:1	c.1156C>T	p.Arg386Cys	missense	Exon 15 of 15	ENSP00000384296.2	Q03154-1

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 751 AN: 152146 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00148 AC: 373 AN: 251320 AF XY: 0.00112

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000906 AC: 1324 AN: 1461862 Hom.: 6 Cov.: 32 AF XY: 0.000818 AC XY: 595 AN XY: 727236

African (AFR) AF: 0.0205 AC: 686 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53394

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000457 AC: 508 AN: 1112008

Other (OTH) AF: 0.00152 AC: 92 AN: 60394

GnomAD4 genome AF: 0.00495 AC: 753 AN: 152264 Hom.: 6 Cov.: 32 AF XY: 0.00514 AC XY: 383 AN XY: 74444

African (AFR) AF: 0.0164 AC: 683 AN: 41544

American (AMR) AF: 0.00235 AC: 36 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68026

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00218 Hom.: 5

Bravo AF: 0.00601

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ACY1-related disorder (1)
-	1	-	Aminoacylase 1 deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.81
Mutation Taster		=48/52	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

dbSNP: rs2229152;

hg19: chr3-52023020;

COSMIC: COSV104397037;

COSMIC: COSV104397037;