10-112408488-G-C

Variant names:

• chr10-112408488-G-C
• rs373960366
• NM_203379.2:c.499G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_203379.2(ACSL5):​c.499G>C​(p.Gly167Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACSL5 NM_203379.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99

Genes affected

ACSL5 (HGNC:16526): (acyl-CoA synthetase long chain family member 5) 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 uterus and spleen, and in trace amounts in normal brain, but has markedly increased levels in malignant gliomas. This gene functions in mediating fatty acid-induced glioma cell growth. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000232934 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSL5	NM_203379.2	c.499G>C	p.Gly167Arg	missense_variant	Exon 6 of 21	ENST00000354655.9	NP_976313.1
ACSL5	NM_016234.4	c.667G>C	p.Gly223Arg	missense_variant	Exon 6 of 21		NP_057318.2
ACSL5	NM_001387037.1	c.667G>C	p.Gly223Arg	missense_variant	Exon 6 of 20		NP_001373966.1
ACSL5	NM_203380.2	c.499G>C	p.Gly167Arg	missense_variant	Exon 6 of 21		NP_976314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSL5	ENST00000354655.9	c.499G>C	p.Gly167Arg	missense_variant	Exon 6 of 21	2	NM_203379.2	ENSP00000346680.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461128 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667G>C (p.G223R) alteration is located in exon 6 (coding exon 6) of the ACSL5 gene. This alteration results from a G to C substitution at nucleotide position 667, causing the glycine (G) at amino acid position 223 to be replaced by an arginine (R). 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	0.91
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;T;.;.;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D;D;.
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Pathogenic	3.9	H;H;.;H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.6	D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.91
MutPred		0.80		Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);.;Gain of solvent accessibility (P = 0.1319);Gain of solvent accessibility (P = 0.1319);
MVP		0.85
MPC		0.72
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.87

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: rs373960366; hg19: chr10-114168246;