12-81139174-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024560.4(ACSS3):c.689G>A(p.Arg230Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACSS3 NM_024560.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.82

Genes affected

ACSS3 (HGNC:24723): (acyl-CoA synthetase short chain family member 3) Enables propionate-CoA ligase activity. Predicted to be involved in ketone body biosynthetic process. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSS3	NM_024560.4	c.689G>A	p.Arg230Lys	missense_variant	4/16	ENST00000548058.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSS3	ENST00000548058.6	c.689G>A	p.Arg230Lys	missense_variant	4/16	1	NM_024560.4	A1
ACSS3	ENST00000261206.7	c.686G>A	p.Arg229Lys	missense_variant	4/16	1		P4
ACSS3	ENST00000548387.1	n.254G>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

May 23, 2023

The c.689G>A (p.R230K) alteration is located in exon 4 (coding exon 4) of the ACSS3 gene. This alteration results from a G to A substitution at nucleotide position 689, causing the arginine (R) at amino acid position 230 to be replaced by a lysine (K). 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	Benign	0.18
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.010	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.28
Sift	Benign	0.28	T;T
Sift4G	Benign	0.91	T;T
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.51		Gain of methylation at R230 (P = 0.0402);.;
MVP		0.35
MPC		0.78
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.40
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-81532953;