11-67646997-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080658.2(ACY3):c.47T>C(p.Val16Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACY3 NM_080658.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36

Genes affected

ACY3 (HGNC:24104): (aminoacylase 3) Predicted to enable aminoacylase activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACY3	NM_080658.2	c.47T>C	p.Val16Ala	missense_variant	3/8	ENST00000255082.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACY3	ENST00000255082.8	c.47T>C	p.Val16Ala	missense_variant	3/8	1	NM_080658.2	P1
ACY3	ENST00000529256.1	c.-245-72T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.47T>C (p.V16A) alteration is located in exon 3 (coding exon 1) of the ACY3 gene. This alteration results from a T to C substitution at nucleotide position 47, causing the valine (V) at amino acid position 16 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.52
MutPred		0.79		Gain of disorder (P = 0.038);
MVP		0.94
MPC		0.58
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.57
gMVP		0.62

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: rs1343708838; hg19: chr11-67414468;