rs150487794

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5PP5

The NM_001243279.3(ACSF3):c.1075G>A(p.Glu359Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,574 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E359Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 0 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 8.90

Publications

21 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:

ENSG00000261546 (HGNC:):

ENSG00000261546 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89114436-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1067556.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 16-89114436-G-A is Pathogenic according to our data. Variant chr16-89114436-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31136.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3 link	c.1075G>A	p.Glu359Lys	missense_variant	Exon 6 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.1075G>A	p.Glu359Lys	missense_variant	Exon 6 of 11	5	NM_001243279.3	ENSP00000479130.1

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000674

AC:

169

AN:

250734

AF XY:

0.000538

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00117

AC:

1706

AN:

1461260

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

811

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33478

American (AMR)

AF:

0.000805

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000568

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00141

AC:

1569

AN:

1112004

Other (OTH)

AF:

0.00113

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

115

231

346

462

577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<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

AF:

0.000716

AC:

109

AN:

152314

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41574

American (AMR)

AF:

0.000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000778

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000684

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined malonic and methylmalonic acidemia

Pathogenic:7

Mar 30, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 14, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ACSF3 c.1075G>A (p.Glu359Lys) results in a conservative amino acid change located in the AMP-dependent synthetase/ligase domain (IPR000873) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00067 in 250734 control chromosomes (gnomAD). c.1075G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Combined Malonic And Methylmalonic Aciduria (CMAMMA) presenting with elevated levels of MA and/or MMA in urine and/or plasma samples (e.g. Alfares_2011, Sloan_2011, Brasil_2018, Levtova_2019). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating the effects of the variant in-vitro. One study showed that cells derived from patients harboring the variant have increased accumulation of MMA in the media, and the expression of wild-type ACSF3 in these cells restores the media MMA to levels similar to controls (e.g. Sloan_2011). Another study demonstrated that cells from a homozygous patient have altered metabolic profiles as determined by Seahorse assays (e.g. Wehbe_2019). The following publications have been ascertained in the context of this evaluation (PMID: 21785126, 30041674, 30740739, 21841779, 31376476). ClinVar contains an entry for this variant (Variation ID: 31136). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 08, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 359 of the ACSF3 protein (p.Glu359Lys). This variant is present in population databases (rs150487794, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with combined malonic and methylmalonic aciduria (PMID: 21785126, 21841779, 26915364, 30740739; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACSF3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3Uncertain:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACSF3: PM3:Very Strong, PM2:Supporting, PP3 -

Feb 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP3, PM3_strong -

Jun 10, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36717752, 21785126, 29858964, 21841779, 26915364, 34426522, 32944792, 31980526, 34440436, 33879512) -

Inborn genetic diseases

Pathogenic:1

Apr 25, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1075G>A (p.E359K) alteration is located in exon 6 (coding exon 4) of the ACSF3 gene. This alteration results from a G to A substitution at nucleotide position 1075, causing the glutamic acid (E) at amino acid position 359 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.067% (188/282126) total alleles studied. This variant has been identified in the homozygous state and/or in conjunction with other ACSF3 variant(s) in individual(s) with features consistent with combined malonic and methylmalonic aciduria; in at least one instance, the variants were identified in trans (Molina-Ramírez, 2022; Barbosa-Gouveia, 2021; Levtova, 2019; de Sain-van der Velden, 2016; Alfares, 2011; Sloan, 2011). This amino acid position is highly conserved in available vertebrate species. In an assay testing ACSF3 function, this variant showed a functionally abnormal result (Koo, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

ACSF3-related disorder

Pathogenic:1

Nov 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ACSF3 c.1075G>A variant is predicted to result in the amino acid substitution p.Glu359Lys. This variant has been reported in both the compound heterozygous and homozygous states in multiple unrelated individuals diagnosed with combined malonic and methylmalonic aciduria (CMAMMA) (Alfares et al. 2011. PubMed ID: 21785126; Sloan et al. 2011. PubMed ID: 21841779; de Sain-van der Velden et al. 2016. PubMed ID: 26915364; Brasil et al. 2018. PubMed ID: 30041674). It has been found to be one of the most commonly reported causative variants in ACSF3 (Levtova et al. 2019. PubMed ID: 30740739). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Methylmalonic acidemia

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.50

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

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

5.0

.;H;H;.;H;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99, 0.98

MVP

0.78

MPC

0.32

ClinPred

0.92

GERP RS

5.0

Varity_R

0.98

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over