16-89154148-C-G

Variant names:

• chr16-89154148-C-G
• rs141090143
• NM_001243279.3:c.1672C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001243279.3(ACSF3):​c.1672C>G​(p.Arg558Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,186 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. R558Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACSF3 NM_001243279.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 25 publications found

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)

ENSG00000308834 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF3	NM_001243279.3	MANE Select	c.1672C>G	p.Arg558Gly	missense	Exon 11 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.1672C>G	p.Arg558Gly	missense	Exon 10 of 10	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.1672C>G	p.Arg558Gly	missense	Exon 11 of 11	NP_777577.2	Q4G176

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF3	ENST00000614302.5	TSL:5 MANE Select	c.1672C>G	p.Arg558Gly	missense	Exon 11 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.877C>G	p.Arg293Gly	missense	Exon 9 of 9	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.1720C>G	p.Arg574Gly	missense	Exon 12 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461186 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726826

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.077
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.69		Loss of MoRF binding (P = 0.0262)
MVP		0.65
MPC		0.34
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.94
gMVP		0.79

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

Other links and lift over

dbSNP: rs141090143; hg19: chr16-89220556;