rs3743979

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001243279.3(ACSF3):c.1114G>A(p.Val372Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 1,612,188 control chromosomes in the GnomAD database, including 436,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V372V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.71 ( 38474 hom., cov: 32)

Exomes 𝑓: 0.74 ( 398474 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.533

Publications

34 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:

ENSG00000261546 (HGNC:):

ENSG00000261546 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.4674323E-6).

BP6

Variant 16-89114475-G-A is Benign according to our data. Variant chr16-89114475-G-A is described in ClinVar as Benign. ClinVar VariationId is 991087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3 link	c.1114G>A	p.Val372Met	missense_variant	Exon 6 of 11	ENST00000614302.5	NP_001230208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5 link	c.1114G>A	p.Val372Met	missense_variant	Exon 6 of 11	5	NM_001243279.3	ENSP00000479130.1

Frequencies

GnomAD3 genomes

AF:

0.707

AC:

107453

AN:

151950

Hom.:

38462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.625

Gnomad AMI

AF:

0.736

Gnomad AMR

AF:

0.761

Gnomad ASJ

AF:

0.744

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.587

Gnomad FIN

AF:

0.778

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.757

Gnomad OTH

AF:

0.729

GnomAD2 exomes

AF:

0.716

AC:

178900

AN:

249890

AF XY:

0.712

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.802

Gnomad ASJ exome

AF:

0.750

Gnomad EAS exome

AF:

0.477

Gnomad FIN exome

AF:

0.781

Gnomad NFE exome

AF:

0.756

Gnomad OTH exome

AF:

0.727

GnomAD4 exome

AF:

0.736

AC:

1074531

AN:

1460120

Hom.:

398474

Cov.:

AF XY:

0.733

AC XY:

532654

AN XY:

726510

show subpopulations

African (AFR)

AF:

0.627

AC:

21004

AN:

33476

American (AMR)

AF:

0.796

AC:

35591

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.747

AC:

19529

AN:

26134

East Asian (EAS)

AF:

0.497

AC:

19714

AN:

39700

South Asian (SAS)

AF:

0.605

AC:

52204

AN:

86254

European-Finnish (FIN)

AF:

0.778

AC:

40268

AN:

51738

Middle Eastern (MID)

AF:

0.755

AC:

4344

AN:

5756

European-Non Finnish (NFE)

AF:

0.754

AC:

838652

AN:

1111964

Other (OTH)

AF:

0.716

AC:

43225

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

19294

38589

57883

77178

96472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20192

40384

60576

80768

100960

<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:

0.707

AC:

107494

AN:

152068

Hom.:

38474

Cov.:

AF XY:

0.705

AC XY:

52435

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.624

AC:

25859

AN:

41460

American (AMR)

AF:

0.761

AC:

11635

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.744

AC:

2580

AN:

3470

East Asian (EAS)

AF:

0.471

AC:

2426

AN:

5150

South Asian (SAS)

AF:

0.588

AC:

2827

AN:

4808

European-Finnish (FIN)

AF:

0.778

AC:

8246

AN:

10600

Middle Eastern (MID)

AF:

0.786

AC:

231

AN:

294

European-Non Finnish (NFE)

AF:

0.757

AC:

51485

AN:

67974

Other (OTH)

AF:

0.726

AC:

1534

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1623

3245

4868

6490

8113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.738

Hom.:

193608

Bravo

AF:

0.703

TwinsUK

AF:

0.755

AC:

2800

ALSPAC

AF:

0.746

AC:

2876

ESP6500AA

AF:

0.624

AC:

2741

ESP6500EA

AF:

0.751

AC:

6462

ExAC

AF:

0.709

AC:

86130

Asia WGS

AF:

0.559

AC:

1944

AN:

3478

EpiCase

AF:

0.761

EpiControl

AF:

0.761

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Combined malonic and methylmalonic acidemia

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Methylmalonic acidemia

Benign:1

May 01, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.1

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.048

T;T;.;T;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.15

.;T;T;.;T;T

MetaRNN

Benign

0.0000025

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;.;L;.;.

PhyloP100

0.53

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.18

N;.;N;N;N;N

REVEL

Benign

0.037

Sift

Benign

0.10

T;.;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.022

B;B;.;B;.;.

Vest4

0.070

MPC

0.18

ClinPred

0.011

GERP RS

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.074

gMVP

0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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