chr16-89114436-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3PM5PP5

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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001467827: 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). The following publications have been ascertained in the context of this evaluation (PMID:21785126, 30041674, 30740739, 21841779, 31376476)." and additional evidence is available in ClinVar. 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 8.90

Publications

21 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACSF3 links:

ENSG00000261546 (HGNC:):

ENSG00000261546 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001467827: 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). The following publications have been ascertained in the context of this evaluation (PMID: 21785126, 30041674, 30740739, 21841779, 31376476).; SCV006211288: "This variant showed a functionally abnormal result (Koo, 2000)."

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89114436-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31136.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243279.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSF3	NM_001243279.3	MANE Select	c.1075G>A	p.Glu359Lys	missense	Exon 6 of 11	NP_001230208.1	Q4G176
ACSF3	NM_001127214.4		c.1075G>A	p.Glu359Lys	missense	Exon 5 of 10	NP_001120686.1	Q4G176
ACSF3	NM_174917.5		c.1075G>A	p.Glu359Lys	missense	Exon 6 of 11	NP_777577.2	Q4G176

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSF3	ENST00000614302.5	TSL:5 MANE Select	c.1075G>A	p.Glu359Lys	missense	Exon 6 of 11	ENSP00000479130.1	Q4G176
ACSF3	ENST00000378345.8	TSL:1	c.280G>A	p.Glu94Lys	missense	Exon 4 of 9	ENSP00000367596.4	F5H5A1
ACSF3	ENST00000871968.1		c.1075G>A	p.Glu359Lys	missense	Exon 6 of 12	ENSP00000542027.1

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

GnomAD2 exomes

AF:

0.000674

AC:

169

AN:

250734

AF XY:

0.000538

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 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

African (AFR)

AF:

0.000269

AC:

AN:

33478

American (AMR)

AF:

0.000805

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000568

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00141

AC:

1569

AN:

1112004

Other (OTH)

AF:

0.00113

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

115

231

346

462

577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<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:

0.000716

AC:

109

AN:

152314

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41574

American (AMR)

AF:

0.000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.00101

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined malonic and methylmalonic acidemia (7)

not provided (4)

ACSF3-related disorder (1)

Inborn genetic diseases (1)

Methylmalonic acidemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.50

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

5.0

PhyloP100

8.9

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.78

MPC

0.32

ClinPred

0.92

GERP RS

5.0

Varity_R

0.98

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over