rs587780270

Positions:

chrX-109682841-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001318510.2(ACSL4):c.284A>G(p.Asn95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,209,920 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

ACSL4
NM_001318510.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.156

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 links:

ACSL4 (HGNC:):

ACSL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13363367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSL4	NM_001318510.2 linkuse as main transcript	c.284A>G	p.Asn95Ser	missense_variant	4/16	ENST00000672401.1	NP_001305439.1	O60488-2Q8TAF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSL4	ENST00000672401.1 linkuse as main transcript	c.284A>G	p.Asn95Ser	missense_variant	4/16		NM_001318510.2	ENSP00000500273.1		O60488-2

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112223

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34363

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183402

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67858

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1097697

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363073

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112223

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34363

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.284A>G (p.N95S) alteration is located in exon 4 (coding exon 2) of the ACSL4 gene. This alteration results from an A to G substitution at nucleotide position 284, causing the asparagine (N) at amino acid position 95 to be replaced by a serine (S). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.284A>G alteration was observed in 0.00055% (1/183402) of total alleles studied, The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.N95 amino acid is not conserved in available vertebrate species and serine (S) is the reference amino acid in some species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.N95S alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 14, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.9

DANN

Benign

0.58

DEOGEN2

Benign

0.070

T;T;.;.;.

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.36

.;T;T;T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.18

N;N;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

0.43

N;N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.77

T;T;T;T;T

Sift4G

Benign

0.74

T;T;T;.;T

Polyphen

0.0010

B;B;.;.;.

Vest4

0.12

MutPred

0.58

Gain of phosphorylation at N136 (P = 0.0774);Gain of phosphorylation at N136 (P = 0.0774);.;.;Gain of phosphorylation at N136 (P = 0.0774);

MVP

0.64

MPC

0.46

ClinPred

0.042

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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