2-222923079-C-A

Position:

• chr2-222923079-C-A

Variant summary

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

The NM_004457.5(ACSL3):​c.1082C>A​(p.Ser361Tyr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACSL3 NM_004457.5 missense, splice_region
• Scores: Splicing: ADA: 0.9853
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSL3	NM_004457.5	c.1082C>A	p.Ser361Tyr	missense_variant, splice_region_variant	10/17	ENST00000357430.8	NP_004448.2
ACSL3	NM_001354158.2	c.1082C>A	p.Ser361Tyr	missense_variant, splice_region_variant	9/16		NP_001341087.1
ACSL3	NM_001354159.2	c.1082C>A	p.Ser361Tyr	missense_variant, splice_region_variant	8/15		NP_001341088.1
ACSL3	NM_203372.3	c.1082C>A	p.Ser361Tyr	missense_variant, splice_region_variant	9/16		NP_976251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSL3	ENST00000357430.8	c.1082C>A	p.Ser361Tyr	missense_variant, splice_region_variant	10/17	1	NM_004457.5	ENSP00000350012.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

May 30, 2023

The c.1082C>A (p.S361Y) alteration is located in exon 10 (coding exon 7) of the ACSL3 gene. This alteration results from a C to A substitution at nucleotide position 1082, causing the serine (S) at amino acid position 361 to be replaced by a tyrosine (Y). 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.44		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.42
MPC		0.94
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.73
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.80
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: chr2-223787797;