rs144681140

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001243279.3(ACSF3):c.1406G>A(p.Arg469Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00631 in 1,614,082 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R469R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0047 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 38 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 1.44

Publications

13 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001243279.3

BP4

Computational evidence support a benign effect (MetaRNN=0.016626418).

BP6

Variant 16-89145306-G-A is Benign according to our data. Variant chr16-89145306-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203601.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00467 (711/152286) while in subpopulation NFE AF = 0.00776 (528/68016). AF 95% confidence interval is 0.00722. There are 1 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 38 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3 link	c.1406G>A	p.Arg469Gln	missense_variant	Exon 9 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.1406G>A	p.Arg469Gln	missense_variant	Exon 9 of 11	5	NM_001243279.3	ENSP00000479130.1		Q4G176

Frequencies

GnomAD3 genomes

AF:

0.00467

AC:

711

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00776

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00431

AC:

1084

AN:

251230

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00701

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00648

AC:

9476

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00637

AC XY:

4635

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33480

American (AMR)

AF:

0.00179

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000650

AC:

AN:

26136

East Asian (EAS)

AF:

0.000982

AC:

AN:

39700

South Asian (SAS)

AF:

0.00369

AC:

318

AN:

86256

European-Finnish (FIN)

AF:

0.00416

AC:

222

AN:

53418

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00763

AC:

8482

AN:

1111930

Other (OTH)

AF:

0.00444

AC:

268

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

644

1287

1931

2574

3218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.00467

AC:

711

AN:

152286

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41564

American (AMR)

AF:

0.00334

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.00394

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00776

AC:

528

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

146

182

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:

0.00617

Hom.:

Bravo

AF:

0.00416

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00458

AC:

556

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined malonic and methylmalonic acidemia

Uncertain:3Benign:1

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACSF3 c.1406G>A; p.Arg469Gln variant (rs144681140), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 203601). This variant is found in the general population with an overall allele frequency of 0.45% (1271/282590 alleles, including 3 homozygotes) in the Genome Aggregation Database. The arginine at codon 469 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.114). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -

Apr 26, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACSF3: BP4, BS2 -

Mar 27, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in a cohort of individuals with hidradenitis suppurativa, but additional clinical information was not included (PMID: 36291580); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36291580) -

Inborn genetic diseases

Benign:1

Jun 21, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ACSF3-related disorder

Benign:1

Dec 19, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

T;T;T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.97

.;D;.;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.70

N;N;N;.;.

PhyloP100

1.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.43

N;.;N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.025

D;.;D;D;D

Sift4G

Benign

0.089

T;T;T;T;T

Polyphen

0.011

B;B;B;.;.

Vest4

0.53

MVP

0.26

MPC

0.059

ClinPred

0.017

GERP RS

3.6

Varity_R

0.093

gMVP

0.49

Mutation Taster

=93/7

polymorphism

(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