2-222916430-A-G

Position:

• chr2-222916430-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004457.5(ACSL3):​c.490A>G​(p.Ile164Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACSL3 NM_004457.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

Genes affected

ACSL3 (HGNC:3570): (acyl-CoA synthetase long chain family member 3) The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme is highly expressed in brain, and preferentially utilizes myristate, arachidonate, and eicosapentaenoate as substrates. The amino acid sequence of this isozyme is 92% identical to that of rat homolog. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACSL3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38855818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSL3	NM_004457.5	c.490A>G	p.Ile164Val	missense_variant	5/17	ENST00000357430.8	NP_004448.2
ACSL3	NM_001354158.2	c.490A>G	p.Ile164Val	missense_variant	4/16		NP_001341087.1
ACSL3	NM_001354159.2	c.490A>G	p.Ile164Val	missense_variant	3/15		NP_001341088.1
ACSL3	NM_203372.3	c.490A>G	p.Ile164Val	missense_variant	4/16		NP_976251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSL3	ENST00000357430.8	c.490A>G	p.Ile164Val	missense_variant	5/17	1	NM_004457.5	ENSP00000350012.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 19, 2024

The c.490A>G (p.I164V) alteration is located in exon 5 (coding exon 2) of the ACSL3 gene. This alteration results from a A to G substitution at nucleotide position 490, causing the isoleucine (I) at amino acid position 164 to be replaced by a valine (V). 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	0.080
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.093
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.10	B;B;.
Vest4		0.46
MutPred		0.60		Loss of methylation at K159 (P = 0.1264);Loss of methylation at K159 (P = 0.1264);.;
MVP		0.36
MPC		0.29
ClinPred		0.90	D
GERP RS		4.1
Varity_R		0.21
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-223781148;