NM_001243279.3:c.1292C>G

Variant names:

• chr16-89133188-C-G
• rs1057520194
• NM_001243279.3:c.1292C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001243279.3(ACSF3):​c.1292C>G​(p.Ser431Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S431F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACSF3 NM_001243279.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83
• Publications: 3 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF3	NM_001243279.3	MANE Select	c.1292C>G	p.Ser431Cys	missense	Exon 8 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.1292C>G	p.Ser431Cys	missense	Exon 7 of 10	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.1292C>G	p.Ser431Cys	missense	Exon 8 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.1292C>G	p.Ser431Cys	missense	Exon 8 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.497C>G	p.Ser166Cys	missense	Exon 6 of 9	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.1340C>G	p.Ser447Cys	missense	Exon 9 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.8
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.53
MutPred		0.67		Gain of catalytic residue at P430 (P = 0.0086)
MVP		0.52
MPC		0.29
ClinPred		0.89	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.81

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: rs1057520194; hg19: chr16-89199596;