dbSNP rs145470870: ACSF3:p.Pro182Arg (chr16-89101226-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001243279.3(ACSF3):c.545C>G(p.Pro182Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. P182L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.540

Publications

0 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08629644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3 link	c.545C>G	p.Pro182Arg	missense_variant	Exon 3 of 11	ENST00000614302.5	NP_001230208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5 link	c.545C>G	p.Pro182Arg	missense_variant	Exon 3 of 11	5	NM_001243279.3	ENSP00000479130.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449258

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33284

American (AMR)

AF:

0.00

AC:

AN:

41754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.00

AC:

AN:

39260

South Asian (SAS)

AF:

0.00

AC:

AN:

85082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106352

Other (OTH)

AF:

0.00

AC:

AN:

59976

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

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.4

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.10

T;T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.42

.;T;T;.

M_CAP

Benign

0.010

MetaRNN

Benign

0.086

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;.;L

PhyloP100

-0.54

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.4

N;.;D;N

REVEL

Benign

0.039

Sift

Benign

0.45

T;.;T;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.048

B;B;.;B

Vest4

0.19

MutPred

0.48

Loss of disorder (P = 0.1266);Loss of disorder (P = 0.1266);Loss of disorder (P = 0.1266);Loss of disorder (P = 0.1266);

MVP

0.15

MPC

0.054

ClinPred

0.14

GERP RS

-3.1

Varity_R

0.031

gMVP

0.50

Mutation Taster

=95/5

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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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