rs1133607

chr16-20483086-C-Gchr16-20483086-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001308172.2(ACSM2A):c.1538C>G(p.Ser513Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,042 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. S513L) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: ACSM2A NM_001308172.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.57

Genes affected

ACSM2A (HGNC:32017): (acyl-CoA synthetase medium chain family member 2A) This gene encodes a mitochondrial acyl-coenzyme A synthetase that is specific for medium chain fatty acids. These enzymes catalyze fatty acid activation, the first step of fatty acid metabolism, through the transfer of acyl-CoA. These enzymes also participate in the glycine conjugation pathway in the detoxification of xenobiotics such as benzoate and ibuprofen. Expression levels of this gene in the kidney may be correlated with kidney function. This gene and its paralog ACSM2B (Gene ID: 348158), both present on chromosome 16, likely arose from a chromosomal duplication event. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSM2A	NM_001308172.2	c.1538C>G	p.Ser513Trp	missense_variant	13/14	ENST00000573854.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSM2A	ENST00000573854.6	c.1538C>G	p.Ser513Trp	missense_variant	13/14	1	NM_001308172.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251472 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74248

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;T;T
Eigen	Benign	0.19
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.87	D;.;.;.;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	0.0030	P;P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.6	D;.;D;.;D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.97	.;D;D;D;D
Vest4		0.41
MutPred		0.49		.;Gain of catalytic residue at L511 (P = 0.0074);Gain of catalytic residue at L511 (P = 0.0074);Gain of catalytic residue at L511 (P = 0.0074);Gain of catalytic residue at L511 (P = 0.0074);
MVP		0.56
MPC		0.76
ClinPred		0.94	D
GERP RS		3.3
Varity_R		0.76
gMVP		0.23

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: rs1133607; hg19: chr16-20494408;