chr16-89101274-T-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5PP3_Strong

The NM_001243279.3(ACSF3):c.593T>A(p.Met198Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000437 in 1,601,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M198R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.70

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89101274-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 31141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

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.593T>A	p.Met198Lys	missense	Exon 3 of 11	NP_001230208.1	Q4G176
ACSF3	NM_001127214.4		c.593T>A	p.Met198Lys	missense	Exon 2 of 10	NP_001120686.1	Q4G176
ACSF3	NM_174917.5		c.593T>A	p.Met198Lys	missense	Exon 3 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.593T>A	p.Met198Lys	missense	Exon 3 of 11	ENSP00000479130.1	Q4G176
ACSF3	ENST00000378345.8	TSL:1	c.-129-1330T>A		intron	N/A	ENSP00000367596.4	F5H5A1
ACSF3	ENST00000871968.1		c.593T>A	p.Met198Lys	missense	Exon 3 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000446

AC:

AN:

224322

AF XY:

0.00000818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1449946

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

720178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33304

American (AMR)

AF:

0.00

AC:

AN:

42720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25958

East Asian (EAS)

AF:

0.00

AC:

AN:

39216

South Asian (SAS)

AF:

0.00

AC:

AN:

84838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000542

AC:

AN:

1106836

Other (OTH)

AF:

0.00

AC:

AN:

59938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41340

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67932

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.092

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.9

PhyloP100

5.7

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.98

Vest4

0.93

MutPred

0.86

Loss of stability (P = 0.0319)

MVP

0.63

MPC

0.35

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.96

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over