rs121912698

chr3-51988821-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R353H) has been classified as Uncertain significance.

• 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:8 U:9
• 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:):

ACMG classification

Verdict is Likely_benign. Variant got -4 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: {Likely_pathogenic=3, Uncertain_significance=9, Pathogenic=3}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03669554).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACY1	NM_000666.3	c.1057C>T	p.Arg353Cys	missense_variant	14/15	ENST00000636358.2
ABHD14A-ACY1	NM_001316331.2	c.1327C>T	p.Arg443Cys	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACY1	ENST00000636358.2	c.1057C>T	p.Arg353Cys	missense_variant	14/15	1	NM_000666.3	P1

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:8 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aminoacylase 1 deficiency Pathogenic:4 Uncertain:4

Likely pathogenic, no assertion criteria provided	clinical testing	Medical Genetics Laboratory, Tarbiat Modares University	Mar 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 12, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 20, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -

not provided Pathogenic:2 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 29, 2023

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 14, 2022

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 (example, Van Coster_2005, Tylki-Szymanska_2010, Sass_2016). The age of presentation was variable ranging from newborn stage for two homozygous case reports (Van Coster_2005, Tylki-Szymanska_2010) to a 63 year old compound heterozygous woman with dystonic symptoms starting at age 12 (example, Sass_2016). These data indicate that the variant is 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 (example Van Coster_2005). The most pronounced variant effect results in <1% of normal Aminoacylase I enzyme activity in lymphoblasts from a homozygous individual. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely Pathogenic, n=5; VUS, n=5) presumably attributed to variability in interpreting the frequency of this variant in population databases. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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
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
MutationTaster	Benign	1.0	A;A;A;A;A;A
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;