16-89145306-G-C

Variant names:

• chr16-89145306-G-C
• rs144681140
• NM_001243279.3:c.1406G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001243279.3(ACSF3):​c.1406G>C​(p.Arg469Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACSF3 NM_001243279.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 13 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF3	NM_001243279.3	MANE Select	c.1406G>C	p.Arg469Pro	missense	Exon 9 of 11	NP_001230208.1
	ACSF3	NM_001127214.4		c.1406G>C	p.Arg469Pro	missense	Exon 8 of 10	NP_001120686.1
	ACSF3	NM_174917.5		c.1406G>C	p.Arg469Pro	missense	Exon 9 of 11	NP_777577.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF3	ENST00000614302.5	TSL:5 MANE Select	c.1406G>C	p.Arg469Pro	missense	Exon 9 of 11	ENSP00000479130.1
	ACSF3	ENST00000378345.8	TSL:1	c.611G>C	p.Arg204Pro	missense	Exon 7 of 9	ENSP00000367596.4
	ACSF3	ENST00000317447.9	TSL:2	c.1406G>C	p.Arg469Pro	missense	Exon 9 of 11	ENSP00000320646.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251230 AF XY: 0.0000147

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000103 Hom.: 6

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.28
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.011	D
Polyphen		0.66	P
Vest4		0.72
MutPred		0.74		Loss of MoRF binding (P = 0.0024)
MVP		0.48
MPC		0.31
ClinPred		0.79	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.87

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: rs144681140; hg19: chr16-89211714;