Variant 10-112425467-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_203379.2(ACSL5):c.1723G>A(p.Gly575Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ACSL5
NM_203379.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

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]

ACSL5 links:

ZDHHC6 (HGNC:19160): (zinc finger DHHC-type palmitoyltransferase 6) Enables palmitoyltransferase activity. Involved in positive regulation of mitochondrial fusion and protein palmitoylation. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC6 links:

ACSL5 (HGNC:):

ACSL5 links:

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ACMG classification

Classification made for transcript

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, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSL5	NM_203379.2 linkuse as main transcript	c.1723G>A	p.Gly575Arg	missense_variant	18/21	ENST00000354655.9	NP_976313.1	Q9ULC5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSL5	ENST00000354655.9 linkuse as main transcript	c.1723G>A	p.Gly575Arg	missense_variant	18/21	2	NM_203379.2	ENSP00000346680.4		Q9ULC5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249214

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134782

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1459486

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.1891G>A (p.G631R) alteration is located in exon 18 (coding exon 18) of the ACSL5 gene. This alteration results from a G to A substitution at nucleotide position 1891, causing the glycine (G) at amino acid position 631 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

0.96

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;.;.;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D;.

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

5.0

H;H;.;H;H

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.6

D;D;D;D;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;.;D

Vest4

0.99

MutPred

0.83

Loss of catalytic residue at G575 (P = 0.0459);Loss of catalytic residue at G575 (P = 0.0459);.;Loss of catalytic residue at G575 (P = 0.0459);Loss of catalytic residue at G575 (P = 0.0459);

MVP

0.84

MPC

0.74

ClinPred

1.0

GERP RS

5.5

Varity_R

0.95

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over