Genetic Variant ACSS1:p.Ser494Phe (chr20-25013634-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032501.4(ACSS1):c.1481C>T(p.Ser494Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000663 in 150,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ACSS1
NM_032501.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95

Variant links:

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]

ACSS1 links:

ENSG00000306411 (HGNC:):

ENSG00000306411 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSS1	NM_032501.4 link	c.1481C>T	p.Ser494Phe	missense_variant	Exon 10 of 14	ENST00000323482.9	NP_115890.2	Q9NUB1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACSS1	ENST00000323482.9 link	c.1481C>T	p.Ser494Phe	missense_variant	Exon 10 of 14	1	NM_032501.4	ENSP00000316924.4	Q9NUB1-1
ACSS1	ENST00000432802.6 link	c.1481C>T	p.Ser494Phe	missense_variant	Exon 10 of 12	2		ENSP00000388793.2	Q9NUB1-4
ACSS1	ENST00000537502.5 link	c.1118C>T	p.Ser373Phe	missense_variant	Exon 9 of 13	2		ENSP00000439304.2	Q9NUB1-3
ENSG00000306411	ENST00000818190.1 link	n.503+4030G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248070

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41044

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5070

South Asian (SAS)

AF:

0.00

AC:

AN:

4728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67518

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1481C>T (p.S494F) alteration is located in exon 10 (coding exon 10) of the ACSS1 gene. This alteration results from a C to T substitution at nucleotide position 1481, causing the serine (S) at amino acid position 494 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

0.18

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.9

.;M;M

PhyloP100

4.9

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.3

.;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

.;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.86

.;.;P

Vest4

0.62

MVP

0.68

MPC

1.3

ClinPred

0.95

GERP RS

5.5

Varity_R

0.66

gMVP

0.81

Mutation Taster

=80/20

polymorphism

(source)

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

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20-25013634-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over