chr2-222922829-C-G

Variant names:

• chr2-222922829-C-G
• rs962840854
• NM_004457.5:c.1078C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004457.5(ACSL3):​c.1078C>G​(p.Gln360Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q360R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ACSL3 NM_004457.5 missense, splice_region
• Scores: Splicing: ADA: 0.8597
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSL3	NM_004457.5	c.1078C>G	p.Gln360Glu	missense_variant, splice_region_variant	Exon 9 of 17	ENST00000357430.8	NP_004448.2
ACSL3	NM_001354158.2	c.1078C>G	p.Gln360Glu	missense_variant, splice_region_variant	Exon 8 of 16		NP_001341087.1
ACSL3	NM_001354159.2	c.1078C>G	p.Gln360Glu	missense_variant, splice_region_variant	Exon 7 of 15		NP_001341088.1
ACSL3	NM_203372.3	c.1078C>G	p.Gln360Glu	missense_variant, splice_region_variant	Exon 8 of 16		NP_976251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSL3	ENST00000357430.8	c.1078C>G	p.Gln360Glu	missense_variant, splice_region_variant	Exon 9 of 17	1	NM_004457.5	ENSP00000350012.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1078C>G (p.Q360E) alteration is located in exon 9 (coding exon 6) of the ACSL3 gene. This alteration results from a C to G substitution at nucleotide position 1078, causing the glutamine (Q) at amino acid position 360 to be replaced by a glutamic acid (E). 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	0.24
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.17
Sift	Benign	0.10	T;T
Sift4G	Benign	0.62	T;T
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.49		Loss of MoRF binding (P = 0.0444);Loss of MoRF binding (P = 0.0444);
MVP		0.44
MPC		0.85
ClinPred		0.91	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.25
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Benign	0.59
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: rs962840854; hg19: chr2-223787547;