chr10-112408509-A-G

Position:

• chr10-112408509-A-G

Variant summary

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

The NM_203379.2(ACSL5):​c.520A>G​(p.Ile174Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACSL5 NM_203379.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

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 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=0.31371367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSL5	NM_203379.2	c.520A>G	p.Ile174Val	missense_variant	6/21	ENST00000354655.9	NP_976313.1
ACSL5	NM_016234.4	c.688A>G	p.Ile230Val	missense_variant	6/21		NP_057318.2
ACSL5	NM_001387037.1	c.688A>G	p.Ile230Val	missense_variant	6/20		NP_001373966.1
ACSL5	NM_203380.2	c.520A>G	p.Ile174Val	missense_variant	6/21		NP_976314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSL5	ENST00000354655.9	c.520A>G	p.Ile174Val	missense_variant	6/21	2	NM_203379.2	ENSP00000346680.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 05, 2024

The c.688A>G (p.I230V) alteration is located in exon 6 (coding exon 6) of the ACSL5 gene. This alteration results from a A to G substitution at nucleotide position 688, causing the isoleucine (I) at amino acid position 230 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	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;T;.;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	.;T;T;T;.
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M;M;.;M;M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.86	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.041	D;D;D;D;D
Sift4G	Uncertain	0.051	T;T;T;T;T
Polyphen		0.56	P;P;P;.;P
Vest4		0.28
MutPred		0.60		Loss of ubiquitination at K177 (P = 0.1079);Loss of ubiquitination at K177 (P = 0.1079);.;Loss of ubiquitination at K177 (P = 0.1079);Loss of ubiquitination at K177 (P = 0.1079);
MVP		0.44
MPC		0.16
ClinPred		0.69	D
GERP RS		4.8
Varity_R		0.15
gMVP		0.37

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: rs1844102537; hg19: chr10-114168267;