dbSNP rs143793502: ACSF3:p.Pro285Gln (chr16-89112123-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_001243279.3(ACSF3):c.854C>A(p.Pro285Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,096,398 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. P285L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.17

Publications

7 publications found

Variant links:

Genes affected

ACSF3 (HGNC:27288): (acyl-CoA synthetase family member 3) This gene encodes a member of the acyl-CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity. Mutations in this gene are a cause of combined malonic and methylmalonic aciduria. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Sep 2013]

ACSF3 Gene-Disease associations (from GenCC):

combined malonic and methylmalonic acidemia
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACSF3 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3 link	c.854C>A	p.Pro285Gln	missense_variant	Exon 5 of 11	ENST00000614302.5	NP_001230208.1	Q4G176

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5 link	c.854C>A	p.Pro285Gln	missense_variant	Exon 5 of 11	5	NM_001243279.3	ENSP00000479130.1		Q4G176

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000857

AC:

AN:

233436

AF XY:

0.0000158

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:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096398

Hom.:

Cov.:

AF XY:

0.00000373

AC XY:

AN XY:

536312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24212

American (AMR)

AF:

0.00

AC:

AN:

28570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15226

East Asian (EAS)

AF:

0.00

AC:

AN:

17202

South Asian (SAS)

AF:

0.00

AC:

AN:

52686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3924

European-Non Finnish (NFE)

AF:

0.00000225

AC:

AN:

890680

Other (OTH)

AF:

0.00

AC:

AN:

39502

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

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.30

.;T;T;.;T;T;.;T

Eigen

Benign

-0.087

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;.;D;D;.;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.71

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.2

.;L;L;.;L;.;.;.

PhyloP100

5.2

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.8

D;D;.;D;D;D;D;D

REVEL

Benign

0.22

Sift

Benign

0.14

T;T;.;T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T;T;T;T

Polyphen

0.47

.;P;P;.;P;.;.;.

Vest4

0.65, 0.73

MutPred

0.53

.;Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);.;Loss of sheet (P = 0.1501);.;.;.;

MVP

0.55

MPC

0.25

ClinPred

0.93

GERP RS

4.5

Varity_R

0.13

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over