3-51984145-C-G

Position:

• chr3-51984145-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000666.3(ACY1):​c.81C>G​(p.Pro27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,960 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (15 hom.)
• Consequence: ACY1 NM_000666.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.54

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-51984145-C-G is Benign according to our data. Variant chr3-51984145-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 721267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.54 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACY1	NM_000666.3	c.81C>G	p.Pro27=	synonymous_variant	2/15	ENST00000636358.2
ABHD14A-ACY1	NM_001316331.2	c.351C>G	p.Pro117=	synonymous_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACY1	ENST00000636358.2	c.81C>G	p.Pro27=	synonymous_variant	2/15	1	NM_000666.3	P1

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00330 AC: 825 AN: 250106 Hom.: 1 AF XY: 0.00356 AC XY: 482 AN XY: 135334

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00655

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00298 AC: 4362 AN: 1461598 Hom.: 15 Cov.: 31 AF XY: 0.00304 AC XY: 2214 AN XY: 727106

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.00577

Gnomad4 NFE exome AF: 0.00299

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74494

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00621

Gnomad4 NFE AF: 0.00388

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00433 Hom.: 1

Bravo AF: 0.00279

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ABHD14A-ACY1: BP4, BP7; ACY1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

ACY1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

This variant is classified as 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
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.8
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs141824939; hg19: chr3-52018161;