12-81078185-C-A

Variant names:

• chr12-81078185-C-A
• rs575214916
• NM_024560.4:c.65C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330243.2(ACSS3):​c.-941C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000574 in 1,394,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: ACSS3 NM_001330243.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1997056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSS3	NM_024560.4	c.65C>A	p.Pro22His	missense_variant	Exon 1 of 16	ENST00000548058.6	NP_078836.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSS3	ENST00000548058.6	c.65C>A	p.Pro22His	missense_variant	Exon 1 of 16	1	NM_024560.4	ENSP00000449535.1
ACSS3	ENST00000261206.7	c.65C>A	p.Pro22His	missense_variant	Exon 1 of 16	1		ENSP00000261206.3
ACSS3	ENST00000549175.1	c.-13-31375C>A		intron_variant	Intron 2 of 3	5		ENSP00000447748.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000574 AC: 8 AN: 1394388 Hom.: 0 Cov.: 31 AF XY: 0.00000580 AC XY: 4 AN XY: 689770

Gnomad4 AFR exome AF: 0.00

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: 0.00000647

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>A (p.P22H) alteration is located in exon 1 (coding exon 1) of the ACSS3 gene. This alteration results from a C to A substitution at nucleotide position 65, causing the proline (P) at amino acid position 22 to be replaced by a histidine (H). 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	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.053
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.71	P;.
Vest4		0.29
MutPred		0.30		Loss of glycosylation at P22 (P = 0.025);Loss of glycosylation at P22 (P = 0.025);
MVP		0.19
MPC		0.83
ClinPred		0.73	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.56

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: rs575214916; hg19: chr12-81471964;