chr12-81078220-C-T

Variant names:

• chr12-81078220-C-T
• rs1287024355
• NM_024560.4:c.100C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14330426).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSS3	NM_024560.4	MANE Select	c.100C>T	p.Leu34Phe	missense	Exon 1 of 16	NP_078836.1	Q9H6R3-1
	ACSS3	NM_001330242.2		c.100C>T	p.Leu34Phe	missense	Exon 1 of 16	NP_001317171.1	A0A0B4J1R2
	ACSS3	NM_001330243.2		c.-906C>T		5_prime_UTR	Exon 1 of 17	NP_001317172.1	Q9H6R3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSS3	ENST00000548058.6	TSL:1 MANE Select	c.100C>T	p.Leu34Phe	missense	Exon 1 of 16	ENSP00000449535.1	Q9H6R3-1
	ACSS3	ENST00000261206.7	TSL:1	c.100C>T	p.Leu34Phe	missense	Exon 1 of 16	ENSP00000261206.3	A0A0B4J1R2
	ACSS3	ENST00000965760.1		c.100C>T	p.Leu34Phe	missense	Exon 1 of 16	ENSP00000635819.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32790

American (AMR) AF: 0.00 AC: 0 AN: 41174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25702

East Asian (EAS) AF: 0.00 AC: 0 AN: 38562

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103966

Other (OTH) AF: 0.00 AC: 0 AN: 59556

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.027
Sift	Benign	0.17	T
Sift4G	Benign	0.081	T
Polyphen		0.070	B
Vest4		0.19
MutPred		0.35		Gain of sheet (P = 0.0149)
MVP		0.26
MPC		0.27
ClinPred		0.32	T
GERP RS		4.6
PromoterAI		0.064	Neutral
Varity_R		0.079
gMVP		0.48
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1287024355; hg19: chr12-81471999; COSMIC: COSV106392418;