12-81134865-A-T

Variant summary

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

The NM_024560.4(ACSS3):c.506A>T(p.Asp169Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACSS3 NM_024560.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

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 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, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSS3	NM_024560.4	c.506A>T	p.Asp169Val	missense_variant	3/16	ENST00000548058.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSS3	ENST00000548058.6	c.506A>T	p.Asp169Val	missense_variant	3/16	1	NM_024560.4	A1
ACSS3	ENST00000261206.7	c.503A>T	p.Asp168Val	missense_variant	3/16	1		P4
ACSS3	ENST00000549175.1	c.182A>T	p.Asp61Val	missense_variant	4/4	5
ACSS3	ENST00000548387.1	n.71A>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444460 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718214

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Jan 05, 2022

The c.506A>T (p.D169V) alteration is located in exon 3 (coding exon 3) of the ACSS3 gene. This alteration results from a A to T substitution at nucleotide position 506, causing the aspartic acid (D) at amino acid position 169 to be replaced by a valine (V). 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	0.79
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-9.0	D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MutPred		0.93		.;Gain of MoRF binding (P = 0.0255);.;
MVP		0.78
MPC		0.94
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.92

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: chr12-81528644;