chr16-20465644-G-A

Position:

• chr16-20465644-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001308172.2(ACSM2A):​c.305G>A​(p.Gly102Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACSM2A NM_001308172.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61

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]

ACSM2A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSM2A	NM_001308172.2	c.305G>A	p.Gly102Asp	missense_variant	3/14	ENST00000573854.6	NP_001295101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSM2A	ENST00000573854.6	c.305G>A	p.Gly102Asp	missense_variant	3/14	1	NM_001308172.2	ENSP00000459451.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461666 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727140

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.305G>A (p.G102D) alteration is located in exon 4 (coding exon 2) of the ACSM2A gene. This alteration results from a G to A substitution at nucleotide position 305, causing the glycine (G) at amino acid position 102 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;T;T;T;T;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.34	T;T;T;.;.;.;T;T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.7	.;.;.;H;H;H;.;H
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.6	.;.;D;.;D;.;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.023	.;.;D;.;D;.;.;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;D;D;.;D
Vest4		0.32, 0.33, 0.33, 0.33, 0.34
MutPred		0.90		.;Loss of catalytic residue at C101 (P = 0.0785);.;Loss of catalytic residue at C101 (P = 0.0785);Loss of catalytic residue at C101 (P = 0.0785);Loss of catalytic residue at C101 (P = 0.0785);Loss of catalytic residue at C101 (P = 0.0785);Loss of catalytic residue at C101 (P = 0.0785);
MVP		0.72
MPC		1.0
ClinPred		0.86	D
GERP RS		1.7
Varity_R		0.45
gMVP		0.76

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: rs745993663; hg19: chr16-20476966;