Genetic Variant ACSS1:p.Arg559Gly (chr20-25012844-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_032501.4(ACSS1):c.1675C>G(p.Arg559Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R559W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACSS1
NM_032501.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.37

Publications

0 publications found

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: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity ACS2L_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSS1	NM_032501.4 link	c.1675C>G	p.Arg559Gly	missense_variant	Exon 11 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.1675C>G	p.Arg559Gly	missense_variant	Exon 11 of 14	1	NM_032501.4	ENSP00000316924.4	Q9NUB1-1
ACSS1	ENST00000537502.5 link	c.1312C>G	p.Arg438Gly	missense_variant	Exon 10 of 13	2		ENSP00000439304.2	Q9NUB1-3
ACSS1	ENST00000432802.6 link	c.1662+13C>G		intron_variant	Intron 11 of 11	2		ENSP00000388793.2	Q9NUB1-4
ENSG00000306411	ENST00000818190.1 link	n.503+3240G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.7

.;H

PhyloP100

1.4

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.9

.;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0020

.;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.98

.;D

Vest4

0.98

MutPred

0.84

.;Gain of glycosylation at S556 (P = 0.0453);

MVP

0.81

MPC

1.7

ClinPred

0.98

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.88

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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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chr20-25012844-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over