rs150487794

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

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 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

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11U:1

Conservation

PhyloP100: 8.90

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-89114436-G-A is Pathogenic according to our data. Variant chr16-89114436-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89114436-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSF3	NM_001243279.3 linkuse as main transcript	c.1075G>A	p.Glu359Lys	missense_variant	6/11	ENST00000614302.5	NP_001230208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5 linkuse as main transcript	c.1075G>A	p.Glu359Lys	missense_variant	6/11	5	NM_001243279.3	ENSP00000479130	P1
	ENST00000562782.1 linkuse as main transcript	n.844C>T		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes

AF:

0.000674

AC:

169

AN:

250734

Hom.:

AF XY:

0.000538

AC XY:

AN XY:

135670

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0000568

Gnomad4 NFE exome

AF:

0.00141

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152314

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00110

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined malonic and methylmalonic acidemia

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2022	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. 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 0.00067 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). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority of submitters classified the variant as either pathogenic (n=3) or likely pathogenic (n=1), and two submitters classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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; Invitae). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 23, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

not provided

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 07, 2023	PP1, PP3, PM3_strong -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2023	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: 21785126, 29858964, 21841779, 26915364, 34426522, 32944792, 31980526, 34440436, 33879512) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ACSF3: PM3:Very Strong, PM2:Supporting, PP3 -

ACSF3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

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

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

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;.;.

MutationTaster

Benign

1.0

D;D;D

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

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