3-51987300-A-G

Variant names:

• chr3-51987300-A-G
• rs323895
• NM_000666.3:c.708-9A>G

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.708-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,613,944 control chromosomes in the GnomAD database, including 4,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2141 hom., cov: 33)
  • Exomes 𝑓: 0.031 (2597 hom.)
• Consequence: ACY1 NM_000666.3 intron
• Scores: Splicing: ADA: 0.00001557
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.88
• Publications: 8 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=-0.89).
• BP6: Variant 3-51987300-A-G is Benign according to our data. Variant chr3-51987300-A-G is described in ClinVar as Benign. ClinVar VariationId is 256757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 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.708-9A>G		intron	N/A	NP_000657.1	Q03154-1
	ABHD14A-ACY1	NM_001316331.2		c.978-9A>G		intron	N/A	NP_001303260.1
	ACY1	NM_001198895.2		c.708-9A>G		intron	N/A	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.708-9A>G		intron	N/A	ENSP00000490149.1	Q03154-1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.1011-9A>G		intron	N/A	ENSP00000420487.1	C9JMV9
	ACY1	ENST00000404366.7	TSL:1	c.708-9A>G		intron	N/A	ENSP00000384296.2	Q03154-1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16245 AN: 152060 Hom.: 2117 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0525

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.0724

Gnomad SAS AF: 0.0681

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0924

GnomAD2 exomes AF: 0.0512 AC: 12863 AN: 250992 AF XY: 0.0470

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.0271

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.0771

Gnomad FIN exome AF: 0.0194

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0419

GnomAD4 exome AF: 0.0315 AC: 46042 AN: 1461766 Hom.: 2597 Cov.: 32 AF XY: 0.0315 AC XY: 22895 AN XY: 727174

African (AFR) AF: 0.320 AC: 10702 AN: 33476

American (AMR) AF: 0.0312 AC: 1397 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 707 AN: 26136

East Asian (EAS) AF: 0.0747 AC: 2966 AN: 39700

South Asian (SAS) AF: 0.0627 AC: 5411 AN: 86256

European-Finnish (FIN) AF: 0.0186 AC: 993 AN: 53318

Middle Eastern (MID) AF: 0.0850 AC: 490 AN: 5768

European-Non Finnish (NFE) AF: 0.0183 AC: 20346 AN: 1111998

Other (OTH) AF: 0.0502 AC: 3030 AN: 60392

GnomAD4 genome AF: 0.107 AC: 16317 AN: 152178 Hom.: 2141 Cov.: 33 AF XY: 0.105 AC XY: 7814 AN XY: 74418

African (AFR) AF: 0.311 AC: 12904 AN: 41464

American (AMR) AF: 0.0524 AC: 802 AN: 15302

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

East Asian (EAS) AF: 0.0720 AC: 373 AN: 5178

South Asian (SAS) AF: 0.0679 AC: 328 AN: 4828

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10620

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0208 AC: 1413 AN: 68002

Other (OTH) AF: 0.0938 AC: 198 AN: 2110

Alfa AF: 0.0500 Hom.: 1051

Bravo AF: 0.120

Asia WGS AF: 0.110 AC: 384 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0231

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.20
PhyloP100		-1.9
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs323895; hg19: chr3-52021316; COSMIC: COSV68343666; COSMIC: COSV68343666;