20-25013978-C-G

Variant names:

• chr20-25013978-C-G
• rs112683865
• NM_032501.4:c.1435G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032501.4(ACSS1):​c.1435G>C​(p.Val479Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V479I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACSS1 NM_032501.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

Genes affected

ACSS1 (HGNC:16091): (acyl-CoA synthetase short chain family member 1) This gene encodes a mitochondrial acetyl-CoA synthetase enzyme. A similar protein in mice plays an important role in the tricarboxylic acid cycle by catalyzing the conversion of acetate to acetyl CoA. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ENSG00000306411 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSS1	NM_032501.4	c.1435G>C	p.Val479Leu	missense_variant	Exon 9 of 14	ENST00000323482.9	NP_115890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSS1	ENST00000323482.9	c.1435G>C	p.Val479Leu	missense_variant	Exon 9 of 14	1	NM_032501.4	ENSP00000316924.4
ACSS1	ENST00000432802.6	c.1435G>C	p.Val479Leu	missense_variant	Exon 9 of 12	2		ENSP00000388793.2
ACSS1	ENST00000537502.5	c.1072G>C	p.Val358Leu	missense_variant	Exon 8 of 13	2		ENSP00000439304.2
ENSG00000306411	ENST00000818190.1	n.504-4299C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Benign	0.96
DEOGEN2	Benign	0.19	.;.;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	.;L;L
PhyloP100		1.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.3	.;N;N
REVEL	Benign	0.097
Sift	Benign	0.035	.;D;D
Sift4G	Benign	0.091	T;T;T
Polyphen		0.24	.;.;B
Vest4		0.49
MutPred		0.46		.;Loss of ubiquitination at K484 (P = 0.0896);Loss of ubiquitination at K484 (P = 0.0896);
MVP		0.25
MPC		0.67
ClinPred		0.090	T
GERP RS		2.0
Varity_R		0.27
gMVP		0.71
Mutation Taster		=96/4	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: rs112683865; hg19: chr20-24994614;