Genetic Variant ACSF3:p.Arg469Gly (chr16-89145305-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001243279.3(ACSF3):c.1405C>G(p.Arg469Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign 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. R469Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.41

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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

PM2

Very rare variant in population databases, with high coverage;

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.1405C>G	p.Arg469Gly	missense	Exon 9 of 11	NP_001230208.1	Q4G176
ACSF3	NM_001127214.4		c.1405C>G	p.Arg469Gly	missense	Exon 8 of 10	NP_001120686.1	Q4G176
ACSF3	NM_174917.5		c.1405C>G	p.Arg469Gly	missense	Exon 9 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.1405C>G	p.Arg469Gly	missense	Exon 9 of 11	ENSP00000479130.1	Q4G176
ACSF3	ENST00000378345.8	TSL:1	c.610C>G	p.Arg204Gly	missense	Exon 7 of 9	ENSP00000367596.4	F5H5A1
ACSF3	ENST00000871968.1		c.1453C>G	p.Arg485Gly	missense	Exon 10 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.032

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.8

PhyloP100

1.4

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0050

Polyphen

0.28

Vest4

0.63

MutPred

0.75

Loss of MoRF binding (P = 0.0133)

MVP

0.46

MPC

0.18

ClinPred

0.94

GERP RS

2.5

Varity_R

0.41

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over