3-51984133-C-G

Variant names:

• chr3-51984133-C-G
• rs34017492
• NM_000666.3:c.69C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000666.3(ACY1):​c.69C>G​(p.Arg23Arg) 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:3
• Conservation: PhyloP100: 0.381
• Publications: 6 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 -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 Benign/Likely_benign. ClinVar VariationId is 773443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.381 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00286 (436/152368) while in subpopulation AMR AF = 0.00411 (63/15310). AF 95% confidence interval is 0.0033. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 29 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.69C>G	p.Arg23Arg	synonymous	Exon 2 of 15	NP_000657.1	Q03154-1
	ABHD14A-ACY1	NM_001316331.2		c.339C>G	p.Arg113Arg	synonymous	Exon 4 of 17	NP_001303260.1
	ACY1	NM_001198895.2		c.69C>G	p.Arg23Arg	synonymous	Exon 2 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.69C>G	p.Arg23Arg	synonymous	Exon 2 of 15	ENSP00000490149.1	Q03154-1
	ACY1	ENST00000404366.7	TSL:1	c.69C>G	p.Arg23Arg	synonymous	Exon 2 of 15	ENSP00000384296.2	Q03154-1
	ABHD14A-ACY1	ENST00000463937.1	TSL:5	c.398-1074C>G		intron	N/A	ENSP00000420487.1	C9JMV9

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

GnomAD2 exomes AF: 0.00310 AC: 776 AN: 250386 AF XY: 0.00315

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 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

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00208 AC: 93 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 694 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86258

European-Finnish (FIN) AF: 0.000790 AC: 42 AN: 53194

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5768

European-Non Finnish (NFE) AF: 0.00265 AC: 2948 AN: 1111978

Other (OTH) AF: 0.00543 AC: 328 AN: 60392

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

African (AFR) AF: 0.000937 AC: 39 AN: 41600

American (AMR) AF: 0.00411 AC: 63 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00300 AC: 204 AN: 68028

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.5
DANN	Benign	0.95
PhyloP100		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs34017492; hg19: chr3-52018149;