chr16-89101274-T-G

Position:

• chr16-89101274-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001243279.3(ACSF3):​c.593T>G​(p.Met198Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000687 in 1,601,830 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 Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ACSF3 NM_001243279.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 16-89101274-T-G is Pathogenic according to our data. Variant chr16-89101274-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31141.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSF3	NM_001243279.3	c.593T>G	p.Met198Arg	missense_variant	3/11	ENST00000614302.5	NP_001230208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5	c.593T>G	p.Met198Arg	missense_variant	3/11	5	NM_001243279.3	ENSP00000479130	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151884 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449946 Hom.: 0 Cov.: 89 AF XY: 0.00000278 AC XY: 2 AN XY: 720178

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151884 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74184

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Combined malonic and methylmalonic acidemia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2024	Variant summary: ACSF3 c.593T>G (p.Met198Arg) results in a non-conservative amino acid change located in the AMP-dependent synthetase/ligase domain (IPR000873) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 224322 control chromosomes (gnomAD). c.593T>G has been reported in the literature in two homozygous individuals affected with Combined Malonic And Methylmalonic Aciduria (Sloan_2011, Kuster_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28924877, 21841779). ClinVar contains an entry for this variant (Variation ID: 31141). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;.
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.8	M;M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D;.;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98	D;D;.;D
Vest4		0.95
MutPred		0.86		Gain of catalytic residue at M198 (P = 0.0108);Gain of catalytic residue at M198 (P = 0.0108);Gain of catalytic residue at M198 (P = 0.0108);Gain of catalytic residue at M198 (P = 0.0108);
MVP		0.62
MPC		0.35
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907121; hg19: chr16-89167682;