chr3-51988821-C-T

Variant names:

• chr3-51988821-C-T
• rs121912698
• NM_000666.3:c.1057C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_000666.3(ACY1):​c.1057C>T​(p.Arg353Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,196 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (15 hom.)
• Consequence: ACY1 NM_000666.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:8
• Conservation: PhyloP100: 3.00

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP5: Variant 3-51988821-C-T is Pathogenic according to our data. Variant chr3-51988821-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18110.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Pathogenic=3, Likely_pathogenic=4}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03669554). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (385/152318) while in subpopulation NFE AF= 0.00398 (271/68034). AF 95% confidence interval is 0.00359. There are 1 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACY1	NM_000666.3	c.1057C>T	p.Arg353Cys	missense_variant	Exon 14 of 15	ENST00000636358.2	NP_000657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACY1	ENST00000636358.2	c.1057C>T	p.Arg353Cys	missense_variant	Exon 14 of 15	1	NM_000666.3	ENSP00000490149.1
ABHD14A-ACY1	ENST00000463937.1	c.1360C>T	p.Arg454Cys	missense_variant	Exon 15 of 16	5		ENSP00000420487.1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00268 AC: 675 AN: 251440 Hom.: 4 AF XY: 0.00286 AC XY: 389 AN XY: 135884

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00360 AC: 5266 AN: 1461878 Hom.: 15 Cov.: 32 AF XY: 0.00356 AC XY: 2592 AN XY: 727236

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00329

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74480

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00374 Hom.: 1

Bravo AF: 0.00263

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00261 AC: 317

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aminoacylase 1 deficiency Pathogenic:5 Uncertain:4

Jun 12, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2020

Medical Genetics Laboratory, Tarbiat Modares University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 20, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2023

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACY1 c.1057C>T (p.Arg353Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 251440 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. Due to the extremely low prevalence of this condition, this frequency does not allow conclusions about variant significance. Furthermore, the clinical/biochemical phenotype, family history or follow-up on the two homozygous individuals reported in the gnomAD database is not known. c.1057C>T has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Aminoacylase I deficiency supported by characteristic biochemical organic acid profiles (Van Coster_2005, Tylki-Szymanska_2010, Sass_2016, Smolka_2023, Kunisetty_2024). The ages of presentation were variable ranging from newborn stage to childhood for homozygous cases reports (Van Coster_2005, Tylki-Szymanska_2010, Smolka_2023, Kunisetty_2024) to a 63 year old compound heterozygous woman with dystonic symptoms starting at age 12 (Sass_2016). These data indicate that the variant is very likely to be associated with disease. However, the possibility of ACY1 deficiency having a pathogenic significance with pleiotropic clinical expression versus simply a biochemical variant phenotype has been speculated (Sass_2006). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal Aminoacylase I enzyme activity in lymphoblasts from a homozygous individual (Van Coster_2005). The following publications have been ascertained in the context of this evaluation (PMID: 26686503, 21414403, 20480396, 16274666, 38502138, 38234346). ClinVar contains an entry for this variant (Variation ID: 18110). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jul 10, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACY1: PM3:Very Strong, PM2:Supporting, PS3:Supporting -

Mar 09, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 353 of the ACY1 protein (p.Arg353Cys). This variant is present in population databases (rs121912698, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with aminoacylase 1 deficiency (PMID: 16274666, 16465618, 17562838, 20480396, 26686503). ClinVar contains an entry for this variant (Variation ID: 18110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACY1 protein function. Experimental studies have shown that this missense change affects ACY1 function (PMID: 21414403, 26686503). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 29, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Aug 02, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1057C>T (p.R353C) alteration is located in exon 14 (coding exon 13) of the ACY1 gene. This alteration results from a C to T substitution at nucleotide position 1057, causing the arginine (R) at amino acid position 353 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.27% (770/282836) total alleles studied, including 4 homozygotes. The highest observed frequency was 0.41% (534/129150) of European (non-Finnish) alleles. This variant has been reported in the homozygous and compound heterozygous state in several individuals with aminoacylase 1 deficiency (Van Coster, 2005; Sass, 2006; Sass, 2007; Tylki-Szymanska, 2010; Sass, 2015). In HEK293 cells, this variant demonstrated a loss of enzyme activity and no protein was detected by western blot compared to wild type (Sommer, 2011). Based on the available evidence, this alteration is classified as likely pathogenic. -

Inborn aminoacylase deficiency Pathogenic:1

Nov 29, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg353Cys variant in ACY1 has been reported in at least 5 homozygous and 2 compound heterozygous individuals with aminoacylase 1 deficiency, including one homozygous individual with an additional finding of Menkes disease (Tylki-Szymanska 2010 PMID: 20480396, Sass 2007 PMID: 17562838, Sass 2006 PMID: 16465618, van Coster 2005 PMID: 16274666, Mauri 2023 PMID: 36936426). There was little consistency in the phenotypes of these individuals or in the severity of the phenotypes, aside from some neurological involvement. This variant has also been It has also been reported by other clinical laboratories in ClinVar (Variation ID 18110) and has been identified in 0.39% (271/68042) European chromosomes by gnomAD (https://gnomad.broadinstitute.org/, v3.1.2), including in 4 homozygous individuals (v2.1.1). In vitro functional studies support an impact on protein function, where HEK cells with the variant show a loss of enzyme activity and no ACY1 protein detection on a western blot compared to wildtype (Sommer 2011 PMID: 21414403), and lymphoblast cell lines generated from a homozygous patient with this variant show <1% of normal aminoacylase I enzyme activity (van Coster 2005 PMID: 16274666). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive aminoacylase 1 deficiency. ACMG/AMP criteria applied: PM3_Strong, PS3_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;D;.;.;.;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.037	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.086	D
MutationAssessor	Pathogenic	3.8	.;H;.;.;.;H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.8	D;.;D;D;D;D;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;.;D;D;D;D;.
Polyphen		1.0	.;D;.;.;.;D;.
Vest4		0.93
MVP		0.76
MPC		0.67
ClinPred		0.14	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.96
gMVP		0.95

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: rs121912698; hg19: chr3-52022837; COSMIC: COSV53686471; COSMIC: COSV53686471;