dbSNP rs141090143: ACSF3:p.Arg558Trp (chr16-89154148-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 14P and 3B. PS3PM5PP5_Very_StrongBP4BS1_SupportingBS2_Supporting

The NM_001243279.3(ACSF3):c.1672C>T(p.Arg558Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,613,416 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000711714: "In vitro functional studies using fibroblasts from affected homozygous and compound heterozygous individuals show increased accumulation of methylmalonic acid fibroblasts, that was restored to normal levels after transfection of a viral vector containing the ACSF3 gene," PMID:21841779" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R558Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 16 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 1.15

Publications

25 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:

ENSG00000308834 (HGNC:):

ENSG00000308834 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000711714: "In vitro functional studies using fibroblasts from affected homozygous and compound heterozygous individuals show increased accumulation of methylmalonic acid fibroblasts, that was restored to normal levels after transfection of a viral vector containing the ACSF3 gene," PMID:21841779; SCV004231900: Functional studies of the p.Arg558Trp variant are supportive of a deleterious effect to the protein showing significantly increased accumulation of methylmalonic acid in patient fibroblasts (Sloan et al., 2011).; SCV005878514: "In vitro functional studies showed that fibroblasts from these four individuals produced 2.4 - 6-times more MMA than control cells, and viral complementation of ACSF3 corrected the cellular metabolic defect (Sloan 2011)." PMID: 21841779

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89154149-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1323847.

PP5

Variant 16-89154148-C-T is Pathogenic according to our data. Variant chr16-89154148-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.015530676). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00471 (6879/1461182) while in subpopulation NFE AF = 0.00582 (6466/1111784). AF 95% confidence interval is 0.0057. There are 16 homozygotes in GnomAdExome4. There are 3251 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1672C>T	p.Arg558Trp	missense	Exon 11 of 11	NP_001230208.1	Q4G176
ACSF3	NM_001127214.4		c.1672C>T	p.Arg558Trp	missense	Exon 10 of 10	NP_001120686.1	Q4G176
ACSF3	NM_174917.5		c.1672C>T	p.Arg558Trp	missense	Exon 11 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.1672C>T	p.Arg558Trp	missense	Exon 11 of 11	ENSP00000479130.1	Q4G176
ACSF3	ENST00000378345.8	TSL:1	c.877C>T	p.Arg293Trp	missense	Exon 9 of 9	ENSP00000367596.4	F5H5A1
ACSF3	ENST00000871968.1		c.1720C>T	p.Arg574Trp	missense	Exon 12 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

408

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00524

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00260

AC:

646

AN:

248458

AF XY:

0.00258

show subpopulations

Gnomad AFR exome

AF:

0.000879

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00114

Gnomad NFE exome

AF:

0.00490

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00471

AC:

6879

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

3251

AN XY:

726826

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33470

American (AMR)

AF:

0.00119

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86024

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00582

AC:

6466

AN:

1111784

Other (OTH)

AF:

0.00417

AC:

252

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

427

854

1280

1707

2134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.00268

AC:

408

AN:

152234

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000915

AC:

AN:

41536

American (AMR)

AF:

0.000589

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00524

AC:

356

AN:

67990

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

109

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:

0.00430

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00257

AC:

312

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00493

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined malonic and methylmalonic acidemia (14)

not provided (5)

ACSF3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Benign

0.12

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.38

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.016

MetaSVM

Uncertain

-0.032

MutationAssessor

Pathogenic

3.7

PhyloP100

1.1

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.51

MVP

0.51

MPC

0.31

ClinPred

0.11

GERP RS

1.4

Varity_R

0.80

gMVP

0.76

Mutation Taster

=76/24

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