NM_001243279.3:c.1672C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting

The NM_001243279.3(ACSF3):c.1672C>T(p.Arg558Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,613,416 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 16 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 1.15

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PP5

Variant 16-89154148-C-T is Pathogenic according to our data. Variant chr16-89154148-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89154148-C-T is described in Lovd as [Pathogenic]. Variant chr16-89154148-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.015530676). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00471 (6879/1461182) while in subpopulation NFE AF= 0.00582 (6466/1111784). AF 95% confidence interval is 0.0057. There are 16 homozygotes in gnomad4_exome. There are 3251 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3 link	c.1672C>T	p.Arg558Trp	missense_variant	Exon 11 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.1672C>T	p.Arg558Trp	missense_variant	Exon 11 of 11	5	NM_001243279.3	ENSP00000479130.1		Q4G176

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

408

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00524

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00260

AC:

646

AN:

248458

Hom.:

AF XY:

0.00258

AC XY:

347

AN XY:

134638

show subpopulations

Gnomad AFR exome

AF:

0.000879

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00114

Gnomad NFE exome

AF:

0.00490

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00471

AC:

6879

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

3251

AN XY:

726826

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.00582

Gnomad4 OTH exome

AF:

0.00417

GnomAD4 genome

AF:

0.00268

AC:

408

AN:

152234

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000915

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00524

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00432

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00257

AC:

312

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00493

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined malonic and methylmalonic acidemia

Pathogenic:12

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PP4 -

Jul 21, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg558Trp variant in the ACSF3 gene has been identified in the homozygous or compound heterozygous state in many individuals diagnosed with CMAMMA (Sloan et al., 2011; Pupavac et al., 2016; Levtova et al., 2019). In several cases, this variant was confirmed to be in trans with another likely pathogenic or pathogenic variant (p.E359K, 1.7 Mb deletion spanning ACSF3), consistent with autosomal recessive inheritance. The p.Arg558Trp variant has been identified in 612/127,754 European non-Finnish chromosomes, including 1 homozygote, by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with an autosomal recessive condition with reduced penetrance. Functional studies of the p.Arg558Trp variant are supportive of a deleterious effect to the protein showing significantly increased accumulation of methylmalonic acid in patient fibroblasts (Sloan et al., 2011). Computational tools also predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg558Trp variant as pathogenic for autosomal recessive combined malonic and methylmalonic aciduria based on the information above. [ACMG evidence codes used: PM3_VeryStrong; PS3_Supporting; PP3] -

Jan 24, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PS3, PM3 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 558 of the ACSF3 protein (p.Arg558Trp). This variant is present in population databases (rs141090143, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 21841779, 26827111; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31134). 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. -

Mar 25, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg558Trp variant in ACSF3 has been reported in >10 homozygous or compound heterozygous individuals with features of combined malonic and methylmalonic acidemia, however some of those patients were asymptomatic and only had elevated methyl malonic acid levels. In several cases, this variant was found with another likely pathogenic or pathogenic variant in ACSF3, and confirmed to be in trans in at least 1 individual (Sloan 2011 PMID: 21841779, Pupavac 2016 PMID: 26827111, Levtova 2019 PMID: 30740739). At least one patient responded to cobalamin treatment (Pupavac 2016 PMID: 26827111). It was found to segregate in one sibling who had elevated methyl malonic acid levels but without clinical concerns (Levtova 2019 PMID: 30740739). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 31134). In addition, this variant has been identified in 0.58% (6822/1179774) of European chromosomes, including 18 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Although the frequency is appreciable, it is consistent with the clinical manifestation of the disease. In vitro functional studies using fibroblasts from affected homozygous and compound heterozygous individuals show increased accumulation of methylmalonic acid fibroblasts, that was restored to normal levels after transfection of a viral vector containing the ACSF3 gene, (Sloan 2011 PMID: 21841779). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive combined malonic and methylmalonic acidemia, however the impact of the biochemical phenotype on clinical features is variable. ACMG/AMP Criteria applied: PM3_VeryStrong, PP4, PP1. -

Dec 04, 2020

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.1672C>T (p.Arg558Trp) results in a non-conservative amino acid change located in the C-terminal domain (IPR025110) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 248458 control chromosomes (gnomAD). The variant, c.1672C>T, has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Combined Malonic and Methylmalonic Aciduria (e.g. Sloan_2011, Pupavac_2016, Levtova_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 30, 2024

Baylor Genetics

Significance: 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

- -

Aug 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACSF3 c.1672C>T;p.Arg558Trp variant (rs141090143, ClinVar Variation ID: 31134) is reported in the literature in the homozygous form, and in trans with other ACSF3 variants in three patients with various neurological problems, ages 16-56. All patients had abnormal levels of methylmalonic acid (MMA) and were diagnosed with combined malonic and methylmalonic aciduria (CMAMMA) (Sloan 2011, Pupavac 2016). This variant has also been identified in individuals with favorable clinical courses but abnormal newborn screening results (Levtova 2019). This variant is found in the general population with an overall allele frequency of 0.26% (724/279804 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). In vitro functional studies showed that fibroblasts from these four individuals produced 2.4 - 6-times more MMA than control cells, and viral complementation of ACSF3 corrected the cellular metabolic defect (Sloan 2011). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.503). Based on the available information, the p.Arg558Trp variant is considered pathogenic. References: Levtova et al. Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort. J Inherit Metab Dis. 2019 Jan;42(1):107-116. PMID: 30740739. Pupavac et al. Added value of next generation gene panel analysis for patients with elevated methylmalonic acid and no clinical diagnosis following functional studies of vitamin B12 metabolism. Mol Genet Metab. 2016 Mar;117(3):363-8. PMID: 26827111. Sloan et al. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Aug 14;43(9):883-6. PMID: 21841779. -

Oct 14, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:5

Aug 14, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

Jan 15, 2025

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: 30609409, 21841779, 26827111, 28468868, 29555771, 29858964, 30041674, 30740739, 30665703, 30487145, 31462756, 31980526, 34426522, 33625768, 33726816, 34662886, 33879512, 17762044, 38536866, 36717752, 31376476, 34440436) -

Oct 06, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM3, PS3, PS4 -

Nov 10, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACSF3-related disorder

Pathogenic:1

May 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACSF3 c.1672C>T variant is predicted to result in the amino acid substitution p.Arg558Trp. 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; Sloan et al. 2011. PubMed ID: 21841779; Pupavac et al. 2016. PubMed ID: 26827111) and has been found to be one of the most commonly reported pathogenic variants in ACSF3 (Levtova et al. 2019. PubMed ID: 30740739).This variant is reported in 0.48% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;D;D;D

Eigen

Benign

0.12

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.38

LIST_S2

Pathogenic

0.99

.;D;.;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Uncertain

-0.032

MutationAssessor

Pathogenic

3.7

H;H;H;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.8

D;.;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.51

MVP

0.51

MPC

0.31

ClinPred

0.11

GERP RS

1.4

Varity_R

0.80

gMVP

0.76

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over