rs387907118

Variant names:

• chr16-89146003-C-T
• rs387907118
• NM_001243279.3:c.1567C>T
• ACSF3 p.Arg523*

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001243279.3(ACSF3):​c.1567C>T​(p.Arg523*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,606,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ACSF3 NM_001243279.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.246
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PP5: Variant 16-89146003-C-T is Pathogenic according to our data. Variant chr16-89146003-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 31135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1567C>T	p.Arg523*	stop_gained	Exon 10 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.1567C>T	p.Arg523*	stop_gained	Exon 9 of 10	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.1567C>T	p.Arg523*	stop_gained	Exon 10 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.1567C>T	p.Arg523*	stop_gained	Exon 10 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.772C>T	p.Arg258*	stop_gained	Exon 8 of 9	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.1615C>T	p.Arg539*	stop_gained	Exon 11 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149658 Hom.: 0 Cov.: 31

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251340 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1457062 Hom.: 0 Cov.: 34 AF XY: 0.0000207 AC XY: 15 AN XY: 724794

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39390

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5730

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1108790

Other (OTH) AF: 0.0000167 AC: 1 AN: 60042

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149658 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 72916

African (AFR) AF: 0.00 AC: 0 AN: 40526

American (AMR) AF: 0.00 AC: 0 AN: 15030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10080

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

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67558

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Combined malonic and methylmalonic acidemia (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.17	N
PhyloP100		0.25
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=16/184	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387907118;

hg19: chr16-89212411;

COSMIC: COSV58081747;

COSMIC: COSV58081747;