rs121912701

Variant names:

• chr3-51989026-G-A
• rs121912701
• NM_000666.3:c.1178G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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. 14/22 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
• Publications: 16 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 -20 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 Benign/Likely_benign. ClinVar VariationId is 18114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152260) while in subpopulation NFE AF = 0.00557 (379/68022). AF 95% confidence interval is 0.00511. There are 1 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.1178G>A	p.Arg393His	missense	Exon 15 of 15	NP_000657.1	Q03154-1
	ABHD14A-ACY1	NM_001316331.2		c.1448G>A	p.Arg483His	missense	Exon 17 of 17	NP_001303260.1
	ACY1	NM_001198895.2		c.1178G>A	p.Arg393His	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.1178G>A	p.Arg393His	missense	Exon 15 of 15	ENSP00000490149.1	Q03154-1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.1481G>A	p.Arg494His	missense	Exon 16 of 16	ENSP00000420487.1	C9JMV9
	ACY1	ENST00000404366.7	TSL:1	c.1178G>A	p.Arg393His	missense	Exon 15 of 15	ENSP00000384296.2	Q03154-1

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

GnomAD2 exomes AF: 0.00367 AC: 921 AN: 250836 AF XY: 0.00363

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 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

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00754 AC: 197 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86258

European-Finnish (FIN) AF: 0.00563 AC: 300 AN: 53320

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.00473 AC: 5260 AN: 1112006

Other (OTH) AF: 0.00392 AC: 237 AN: 60390

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

African (AFR) AF: 0.000867 AC: 36 AN: 41542

American (AMR) AF: 0.00137 AC: 21 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00557 AC: 379 AN: 68022

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00458 Hom.: 6

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ACY1-related disorder (1)
1	-	-	Aminoacylase 1 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.47	N
PhyloP100		0.093
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.27	T
Sift4G	Benign	0.18	T
Polyphen		0.99	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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs121912701; hg19: chr3-52023042;