3-51984133-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000666.3(ACY1):c.69C>G(p.Arg23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,613,992 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (29 hom.)
• Consequence: ACY1 NM_000666.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.381

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-51984133-C-G is Benign according to our data. Variant chr3-51984133-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 773443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-51984133-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.381 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00299 (4376/1461624) while in subpopulation MID AF= 0.0182 (105/5768). AF 95% confidence interval is 0.0154. There are 29 homozygotes in gnomad4_exome. There are 2204 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• 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.69C>G	p.Arg23=	synonymous_variant	2/15	ENST00000636358.2
ABHD14A-ACY1	NM_001316331.2	c.339C>G	p.Arg113=	synonymous_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACY1	ENST00000636358.2	c.69C>G	p.Arg23=	synonymous_variant	2/15	1	NM_000666.3	P1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152250 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00310 AC: 776 AN: 250386 Hom.: 4 AF XY: 0.00315 AC XY: 427 AN XY: 135480

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.000976

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00299 AC: 4376 AN: 1461624 Hom.: 29 Cov.: 31 AF XY: 0.00303 AC XY: 2204 AN XY: 727102

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.000790

Gnomad4 NFE exome AF: 0.00265

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152368 Hom.: 1 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74508

Gnomad4 AFR AF: 0.000937

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00300

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00481 Hom.: 2

Bravo AF: 0.00322

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ACY1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	9.5
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34017492; hg19: chr3-52018149;