dbSNP rs797045215: ACSL4:p.Met487Leu (chrX-109663334-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001318510.2(ACSL4):c.1459A>T(p.Met487Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M487V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

ACSL4
NM_001318510.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.09

Publications

0 publications found

Variant links:

Genes affected

ACSL4 (HGNC:3571): (acyl-CoA synthetase long chain family member 4) 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 preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the cognitive disability or Alport syndrome. Alternative splicing of this gene generates multiple transcript variants. [provided by RefSeq, Jan 2016]

ACSL4 Gene-Disease associations (from GenCC):

non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, Illumina, Orphanet
intellectual disability, X-linked 63
Inheritance: XL Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACSL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39900604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSL4	NM_001318510.2 link	c.1459A>T	p.Met487Leu	missense_variant	Exon 13 of 16	ENST00000672401.1	NP_001305439.1	O60488-2Q8TAF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSL4	ENST00000672401.1 link	c.1459A>T	p.Met487Leu	missense_variant	Exon 13 of 16		NM_001318510.2	ENSP00000500273.1		O60488-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096062

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26354

American (AMR)

AF:

0.0000284

AC:

AN:

35187

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30171

South Asian (SAS)

AF:

0.00

AC:

AN:

54062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840250

Other (OTH)

AF:

0.00

AC:

AN:

46020

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.0093

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.098

T;T;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.47

N;N;.

PhyloP100

5.1

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.0050

B;B;.

Vest4

0.34

MutPred

0.68

Loss of ubiquitination at K532 (P = 0.0863);Loss of ubiquitination at K532 (P = 0.0863);.;

MVP

0.88

MPC

0.54

ClinPred

0.70

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.78

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over