3-51986395-C-T

Variant names:

• chr3-51986395-C-T
• rs323893
• NM_000666.3:c.437-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000666.3(ACY1):​c.437-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,607,980 control chromosomes in the GnomAD database, including 4,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2159 hom., cov: 32)
  • Exomes 𝑓: 0.032 (2632 hom.)
• Consequence: ACY1 NM_000666.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.33
• Publications: 9 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 (BayesDel_noAF=-0.88).
• BP6: Variant 3-51986395-C-T is Benign according to our data. Variant chr3-51986395-C-T is described in ClinVar as Benign. ClinVar VariationId is 256754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

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.437-20C>T		intron	N/A	NP_000657.1
	ABHD14A-ACY1	NM_001316331.2		c.707-20C>T		intron	N/A	NP_001303260.1
	ACY1	NM_001198895.2		c.437-20C>T		intron	N/A	NP_001185824.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACY1	ENST00000636358.2	TSL:1 MANE Select	c.437-20C>T		intron	N/A	ENSP00000490149.1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.740-20C>T		intron	N/A	ENSP00000420487.1
	ACY1	ENST00000404366.7	TSL:1	c.437-20C>T		intron	N/A	ENSP00000384296.2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16259 AN: 151878 Hom.: 2135 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0524

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.0703

Gnomad SAS AF: 0.0675

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0920

GnomAD2 exomes AF: 0.0513 AC: 12145 AN: 236718 AF XY: 0.0472

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.0272

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.0768

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0427

GnomAD4 exome AF: 0.0315 AC: 45875 AN: 1455984 Hom.: 2632 Cov.: 33 AF XY: 0.0315 AC XY: 22773 AN XY: 723778

African (AFR) AF: 0.325 AC: 10842 AN: 33342

American (AMR) AF: 0.0313 AC: 1369 AN: 43772

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 701 AN: 25968

East Asian (EAS) AF: 0.0742 AC: 2935 AN: 39562

South Asian (SAS) AF: 0.0627 AC: 5357 AN: 85426

European-Finnish (FIN) AF: 0.0188 AC: 995 AN: 52984

Middle Eastern (MID) AF: 0.0837 AC: 474 AN: 5660

European-Non Finnish (NFE) AF: 0.0182 AC: 20172 AN: 1109106

Other (OTH) AF: 0.0504 AC: 3030 AN: 60164

GnomAD4 genome AF: 0.107 AC: 16331 AN: 151996 Hom.: 2159 Cov.: 32 AF XY: 0.105 AC XY: 7812 AN XY: 74312

African (AFR) AF: 0.314 AC: 12945 AN: 41288

American (AMR) AF: 0.0523 AC: 800 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3470

East Asian (EAS) AF: 0.0699 AC: 361 AN: 5166

South Asian (SAS) AF: 0.0673 AC: 325 AN: 4826

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10624

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0207 AC: 1408 AN: 68014

Other (OTH) AF: 0.0934 AC: 197 AN: 2110

Alfa AF: 0.0438 Hom.: 800

Bravo AF: 0.122

Asia WGS AF: 0.110 AC: 384 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.023
DANN	Benign	0.52
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs323893; hg19: chr3-52020411; COSMIC: COSV68344565; COSMIC: COSV68344565;