rs121912699

chr3-51987188-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000666.3(ACY1):c.699A>C(p.Glu233Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ACY1
NM_000666.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.66

Variant links:

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]

ACY1 links:

ABHD14A-ACY1 (HGNC:):

ABHD14A-ACY1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-51987188-A-C is Pathogenic according to our data. Variant chr3-51987188-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACY1	NM_000666.3 linkuse as main transcript	c.699A>C	p.Glu233Asp	missense_variant	10/15	ENST00000636358.2
ABHD14A-ACY1	NM_001316331.2 linkuse as main transcript	c.969A>C	p.Glu323Asp	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACY1	ENST00000636358.2 linkuse as main transcript	c.699A>C	p.Glu233Asp	missense_variant	10/15	1	NM_000666.3	P1	Q03154-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251438

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000200

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aminoacylase 1 deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

The c.699A>C (p.E233D) alteration is located in exon 10 (coding exon 9) of the ACY1 gene. This alteration results from a A to C substitution at nucleotide position 699, causing the glutamic acid (E) at amino acid position 233 to be replaced by an aspartic acid (D). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (24/251438) total alleles studied. The highest observed frequency was 0.018% (21/113738) of European (non-Finnish) alleles. This variant has been detected in conjunction with a second ACY1 variant in multiple individuals with Aminoacylase I deficiency (Sass, 2006; Alessandrì, 2014; Alessandrì, 2018). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs aminoacylase enzyme activity (Sommer, 2011). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Uncertain

0.020

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.98

D;T;D;.;D;D;D;D

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.63

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.49

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.5

N;.;.;.;D;N;D;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.026

D;.;.;.;D;D;D;.

Sift4G

Uncertain

0.013

D;.;.;.;D;D;D;.

Polyphen

0.99

.;.;.;D;.;.;D;.

Vest4

0.77

MVP

0.82

MPC

0.51

ClinPred

0.76

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over