Genetic Variant ACSL1:p.Glu503Lys (chr4-184763181-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001995.5(ACSL1):c.1507G>A(p.Glu503Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ACSL1
NM_001995.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.14

Variant links:

Genes affected

ACSL1 (HGNC:3569): (acyl-CoA synthetase long chain family member 1) 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. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACSL1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05823168).

BP6

Variant 4-184763181-C-T is Benign according to our data. Variant chr4-184763181-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3825328.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSL1	NM_001995.5 link	c.1507G>A	p.Glu503Lys	missense_variant	Exon 16 of 21	ENST00000281455.7	NP_001986.2	P33121-1A8K9T3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSL1	ENST00000281455.7 link	c.1507G>A	p.Glu503Lys	missense_variant	Exon 16 of 21	1	NM_001995.5	ENSP00000281455.2		P33121-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251110

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 25, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.21

T;T;T;T;T;.;T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.84

.;T;.;T;.;T;T;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.058

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.82

.;.;N;.;N;.;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.42

N;.;N;N;N;N;N;N

REVEL

Benign

0.079

Sift

Benign

0.82

T;.;T;T;T;T;T;T

Sift4G

Benign

0.41

T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;B;.;B;B;B;.

Vest4

0.17

MutPred

0.46

.;.;Gain of ubiquitination at E503 (P = 0.017);.;Gain of ubiquitination at E503 (P = 0.017);.;Gain of ubiquitination at E503 (P = 0.017);Gain of ubiquitination at E503 (P = 0.017);

MVP

0.21

MPC

0.35

ClinPred

0.35

GERP RS

-0.092

Varity_R

0.022

gMVP

0.63

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