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GeneBe

12-81134850-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024560.4(ACSS3):c.491G>A(p.Gly164Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000114 in 1,581,766 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 0.000026 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

ACSS3
NM_024560.4 missense

Scores

2
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACSS3NM_024560.4 linkuse as main transcriptc.491G>A p.Gly164Asp missense_variant 3/16 ENST00000548058.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACSS3ENST00000548058.6 linkuse as main transcriptc.491G>A p.Gly164Asp missense_variant 3/161 NM_024560.4 A1Q9H6R3-1
ACSS3ENST00000261206.7 linkuse as main transcriptc.488G>A p.Gly163Asp missense_variant 3/161 P4
ACSS3ENST00000549175.1 linkuse as main transcriptc.167G>A p.Gly56Asp missense_variant 4/45
ACSS3ENST00000548387.1 linkuse as main transcriptn.56G>A non_coding_transcript_exon_variant 1/32

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152080
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000418
AC:
1
AN:
239176
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
129376
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000905
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000979
AC:
14
AN:
1429686
Hom.:
0
Cov.:
30
AF XY:
0.0000113
AC XY:
8
AN XY:
710324
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000128
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152080
Hom.:
0
Cov.:
30
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000330
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 30, 2022The c.491G>A (p.G164D) alteration is located in exon 3 (coding exon 3) of the ACSS3 gene. This alteration results from a G to A substitution at nucleotide position 491, causing the glycine (G) at amino acid position 164 to be replaced by an aspartic acid (D). 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
0.13
BayesDel_addAF
Uncertain
0.052
T
BayesDel_noAF
Benign
-0.16
Cadd
Benign
23
Dann
Uncertain
0.98
DEOGEN2
Benign
0.38
T;T;T
Eigen
Benign
-0.013
Eigen_PC
Benign
0.029
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D;T
M_CAP
Benign
0.047
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Uncertain
-0.27
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-6.5
D;D;D
REVEL
Uncertain
0.32
Sift
Uncertain
0.016
D;D;D
Sift4G
Uncertain
0.018
D;D;D
Polyphen
0.048
.;B;.
Vest4
0.50, 0.50
MutPred
0.87
.;Gain of relative solvent accessibility (P = 0.0082);.;
MVP
0.60
MPC
0.34
ClinPred
0.94
D
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.55
gMVP
0.86

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773886334; hg19: chr12-81528629; COSMIC: COSV105036459; API