12-81078220-C-T

Variant summary

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

The NM_024560.4(ACSS3):c.100C>T(p.Leu34Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACSS3 NM_024560.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

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=0.14330426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSS3	NM_024560.4	c.100C>T	p.Leu34Phe	missense_variant	1/16	ENST00000548058.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSS3	ENST00000548058.6	c.100C>T	p.Leu34Phe	missense_variant	1/16	1	NM_024560.4	A1
ACSS3	ENST00000261206.7	c.100C>T	p.Leu34Phe	missense_variant	1/16	1		P4
ACSS3	ENST00000549175.1	c.-13-31340C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440072 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715440

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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 29, 2024

The c.100C>T (p.L34F) 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 100, causing the leucine (L) at amino acid position 34 to be replaced by a phenylalanine (F). 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	0.092
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.027
Sift	Benign	0.17	T;T
Sift4G	Benign	0.081	T;T
Polyphen		0.070	B;.
Vest4		0.19
MutPred		0.35		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.26
MPC		0.27
ClinPred		0.32	T
GERP RS		4.6
Varity_R		0.079
gMVP		0.48

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: rs1287024355; hg19: chr12-81471999;