rs150487794

chr16-89114436-G-Achr16-89114436-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_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 (★★). 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1
• Conservation: PhyloP100: 8.90

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89114436-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 [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	UniProt
ACSF3	NM_001243279.3	c.1075G>A	p.Glu359Lys	missense_variant	6/11	ENST00000614302.5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152196 Hom.: 1 Cov.: 33

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.: 0 AF XY: 0.000538 AC XY: 73 AN XY: 135670

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.: 0 Cov.: 44 AF XY: 0.00112 AC XY: 811 AN XY: 726956

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.: 1 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74472

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.: 1

Bravo AF: 0.000778

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000684 AC: 83

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000830

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined malonic and methylmalonic acidemia Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -
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. -

not provided Pathogenic:3 Uncertain: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, criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;.;D;D;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
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	D
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

Other links and lift over

dbSNP: rs150487794; hg19: chr16-89180844; COSMIC: COSV58082354;