rs121912701

chr3-51989026-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000666.3(ACY1):c.1178G>A(p.Arg393His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00411 in 1,614,040 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (12 hom.)
• Consequence: ACY1 NM_000666.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 0.0930

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06689611).
• BP6: Variant 3-51989026-G-A is Benign according to our data. Variant chr3-51989026-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 18114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACY1	NM_000666.3	c.1178G>A	p.Arg393His	missense_variant	15/15	ENST00000636358.2
ABHD14A-ACY1	NM_001316331.2	c.1448G>A	p.Arg483His	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACY1	ENST00000636358.2	c.1178G>A	p.Arg393His	missense_variant	15/15	1	NM_000666.3	P1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 512 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00367 AC: 921 AN: 250836 Hom.: 3 AF XY: 0.00363 AC XY: 492 AN XY: 135608

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00666

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00509

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00419 AC: 6127 AN: 1461780 Hom.: 12 Cov.: 32 AF XY: 0.00399 AC XY: 2905 AN XY: 727188

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00754

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00563

Gnomad4 NFE exome AF: 0.00473

Gnomad4 OTH exome AF: 0.00392

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00309 AC XY: 230 AN XY: 74436

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00557

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00485 Hom.: 4

Bravo AF: 0.00296

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00397 AC: 482

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ABHD14A-ACY1: BP4 -

Aminoacylase 1 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 12, 2007

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 14, 2016

- -

ACY1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.80	T;.;T;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.067	T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	0.0000016	A;A;A;A;A;A
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;.;N;N;N;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.27	T;.;D;D;T;D;.
Sift4G	Benign	0.18	T;.;T;T;T;T;.
Polyphen		0.99	.;D;.;.;.;D;.
Vest4		0.71
MVP		0.41
MPC		0.62
ClinPred		0.043	T
GERP RS		-0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.54

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: rs121912701; hg19: chr3-52023042;