Genetic Variant ACSS3:p.Pro136Thr (chr12-81109654-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_024560.4(ACSS3):c.406C>A(p.Pro136Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,696 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P136A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACSS3
NM_024560.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.37

Publications

0 publications found

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]

ACSS3 links:

ACSS3-AS1 (HGNC:58286):

ACSS3-AS1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSS3	NM_024560.4	MANE Select	c.406C>A	p.Pro136Thr	missense	Exon 2 of 16	NP_078836.1	Q9H6R3-1
ACSS3	NM_001330242.2		c.403C>A	p.Pro135Thr	missense	Exon 2 of 16	NP_001317171.1	A0A0B4J1R2
ACSS3	NM_001330243.2		c.-600C>A		5_prime_UTR	Exon 2 of 17	NP_001317172.1	Q9H6R3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSS3	ENST00000548058.6	TSL:1 MANE Select	c.406C>A	p.Pro136Thr	missense	Exon 2 of 16	ENSP00000449535.1	Q9H6R3-1
ACSS3	ENST00000261206.7	TSL:1	c.403C>A	p.Pro135Thr	missense	Exon 2 of 16	ENSP00000261206.3	A0A0B4J1R2
ACSS3	ENST00000965760.1		c.406C>A	p.Pro136Thr	missense	Exon 2 of 16	ENSP00000635819.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458696

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725520

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

44416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39508

South Asian (SAS)

AF:

0.00

AC:

AN:

85400

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110628

Other (OTH)

AF:

0.00

AC:

AN:

60262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.49

MutationAssessor

Benign

2.0

PhyloP100

5.4

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.7

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.79

MutPred

0.43

Gain of phosphorylation at P136 (P = 0.1009)

MVP

0.54

MPC

0.82

ClinPred

1.0

GERP RS

6.1

Varity_R

0.84

gMVP

0.73

Mutation Taster

=16/84

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over