12-81078359-C-T

Variant names:

• chr12-81078359-C-T
• rs1217783472
• NM_024560.4:c.239C>T

Variant summary

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

The NM_001330243.2(ACSS3):​c.-767C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ACSS3 NM_001330243.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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=0.24620217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSS3	NM_024560.4	c.239C>T	p.Ala80Val	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.239C>T	p.Ala80Val	missense_variant	Exon 1 of 16	1	NM_024560.4	ENSP00000449535.1
ACSS3	ENST00000261206.7	c.239C>T	p.Ala80Val	missense_variant	Exon 1 of 16	1		ENSP00000261206.3
ACSS3	ENST00000549175.1	c.-13-31201C>T		intron_variant	Intron 2 of 3	5		ENSP00000447748.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.239C>T (p.A80V) alteration is located in exon 1 (coding exon 1) of the ACSS3 gene. This alteration results from a C to T substitution at nucleotide position 239, causing the alanine (A) at amino acid position 80 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	Benign	0.091
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	0.0087
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.30	N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.13
Sift	Benign	0.13	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.58	P;.
Vest4		0.37
MutPred		0.44		Gain of stability (P = 0.0227);Gain of stability (P = 0.0227);
MVP		0.17
MPC		0.29
ClinPred		0.84	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.52

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: rs1217783472; hg19: chr12-81472138;