rs138680796

Variant names:

• chr16-89145311-C-T
• rs138680796
• NM_001243279.3:c.1411C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP3 PP5 BP4

The NM_001243279.3(ACSF3):​c.1411C>T​(p.Arg471Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ACSF3 NM_001243279.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:4
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ACSF3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 16-89145311-C-T is Pathogenic according to our data. Variant chr16-89145311-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31137.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37387383). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3	c.1411C>T	p.Arg471Trp	missense_variant	Exon 9 of 11	ENST00000614302.5	NP_001230208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5	c.1411C>T	p.Arg471Trp	missense_variant	Exon 9 of 11	5	NM_001243279.3	ENSP00000479130.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000318 AC: 80 AN: 251262 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.000186 AC XY: 135 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000704 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined malonic and methylmalonic acidemia Pathogenic:4 Uncertain:3

Aug 14, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACSF3 c.1411C>T; p.Arg471Trp variant (rs138680796), is reported in the literature in the homozygous state in two individuals affected with combined malonic and methylmalonic aciduria (CMAMMA) (Alfares 2011, Sloan 2011). This variant is found in the Ashkenazi Jewish population with an overall allele frequency of 0.71% (73/10360 alleles) in the Genome Aggregation Database, though at least one affected individual with this variant was of Ashkenazi descent (Alfares 2011). The arginine at codon 471 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Another variant at the same codon (p.Arg471Gln) was also reported in an individual with CMAMMA, though its clinical significance remains uncertain (Sloan 2011). Given the lack of clinical and functional data, the significance of the p.Arg471Trp variant is uncertain at this time. References: Alfares A et al. Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype. J Med Genet. 2011 Sep;48(9):602-5. Sloan JL et al. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Aug 14;43(9):883-6. -

Aug 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with tryptophan at codon 471 of the ACSF3 protein (p.Arg471Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs138680796, ExAC 0.04%). This variant has been observed in individuals affected with combined malonic and methylmalonic aciduria (PMID: 29858964, 21841779, 21785126). ClinVar contains an entry for this variant (Variation ID: 31137). Experimental studies have shown that this missense change disrupts ACSF3 protein function in vitro (PMID: 9030548). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 22, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACSF3 c.1411C>T (p.Arg471Trp) results in a non-conservative amino acid change located in the AMP-dependent synthetase/ligase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251262 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACSF3 causing Combined Malonic And Methylmalonic Aciduria (0.00032 vs 0.0058), allowing no conclusion about variant significance. c.1411C>T has been reported in the literature in two individuals in the homozygous state affected with Combined Malonic And Methylmalonic Aciduria, however with benign clinical courses (ie. elevated MA and MMA levels in urine and plasma, without other major clinical features; Alfares_2011, Sloan_2012). In a functional study, fibroblast cell lines from a patient homozygous for the variant displayed elevated MA and MMA in culture media, therefore recapitulating the biochemical outcome observed in the two reported patients (Wehbe_2019). Additionally, the equivalent residue in E. coli was shown to result in the complete loss of fatty acyl-CoA synthetase enzymatic activity (Black_1997). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four labs classified the variant as VUS while one classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Apr 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:2

Dec 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies of the equivalent residue in E. coli resulted in complete loss of fatty acyl-CoA synthetase enzymatic activity (Black et al., 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 29858964, 21841779, 9030548, 21785126) -

Mar 08, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ACSF3 gene demonstrated a sequence change, c.1411C>T, in exon 9 that results in an amino acid change, p.Arg471Trp. The p.Arg471Trp change affects a moderately conserved amino acid residue located in a domain of the ACSF3 protein that is known to be functional. The p.Arg471Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL). This sequence change has been described in the gnomAD database with a low global population frequency of 0.03%, but a relatively high frequency of 0.7% in the Ashkenazi Jewish population (dbSNP rs138680796). The p.Arg471Trp change has been identified in the homozygous state in an Ashkenazi Jewish patient with combined malonic and methylmalonic aciduria but who was clinically asymptomatic at 14 years of age (PMID: 21785126). The patient was initially identified by newborn screening (PMID: 10356133). PMID: 21841779 reported a 66 year old woman who is apparently homozygous for the p.Arg471Trp change who exhibited elevated malonic and methylmalonic acid in plasma and urine. This individual reported incontinence and mild memory issues. Additionally, a different sequence changes affecting the same amino acid residue (p.Arg471Gln) has been described in the compound heterozygous state with a second missense variant a patient with combined malonic and methylmalonic aciduria (PMID: 21841779). Although the p.Arg471Trp change in the homozygous state has not been reported to cause a significant clinical phenotype to date, it has not been reported in compound heterozygous state with a potentially more damaging mutation and therefore the full spectrum of disease associated with the p.Arg471Gln change is not currently known. -

Inborn genetic diseases Pathogenic:1

Oct 04, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1411C>T (p.R471W) alteration is located in exon 9 (coding exon 7) of the ACSF3 gene. This alteration results from a C to T substitution at nucleotide position 1411, causing the arginine (R) at amino acid position 471 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.029% (82/282622) total alleles studied. The highest observed frequency was 0.705% (73/10360) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state in individuals with elevated plasma MMA, plasma MA, and/or elevated urine MMA, urine MA, with lack of expected metabolic disease symptoms (Alfares, 2011; Sloan, 2011). Another alteration at the same codon, c.1412G>A (p.R471Q), has been detected in in one individual with hypoglycemia, acidosis, poor weight gain, diarrhea episodes, and biochemical findings consistent with combined malonic and methylmalonic aciduria (Sloan, 2011). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Methylmalonic acidemia Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;D;D;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;H;H;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.0	D;.;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.98
MVP		0.64
MPC		0.31
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.91

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: rs138680796; hg19: chr16-89211719; COSMIC: COSV58081791; COSMIC: COSV58081791;