rs200451158

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001318510.2(ACSL4):c.1325A>G(p.Tyr442Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,205,232 control chromosomes in the GnomAD database, including 2 homozygotes. There are 205 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., 16 hem., cov: 23)

Exomes 𝑓: 0.00047 ( 1 hom. 189 hem. )

Consequence

ACSL4
NM_001318510.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 2.28

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07525155).

BP6

Variant X-109665485-T-C is Benign according to our data. Variant chrX-109665485-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194058.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=4, Uncertain_significance=1}. Variant chrX-109665485-T-C is described in Lovd as [Likely_benign]. Variant chrX-109665485-T-C is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSL4	NM_001318510.2 linkuse as main transcript	c.1325A>G	p.Tyr442Cys	missense_variant	12/16	ENST00000672401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSL4	ENST00000672401.1 linkuse as main transcript	c.1325A>G	p.Tyr442Cys	missense_variant	12/16		NM_001318510.2	P4	O60488-2

Frequencies

GnomAD3 genomes

AF:

0.000483

AC:

AN:

111886

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

34044

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000790

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.000458

AC:

AN:

183308

Hom.:

AF XY:

0.000590

AC XY:

AN XY:

67824

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00107

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000315

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000466

AC:

509

AN:

1093346

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

189

AN XY:

358968

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.000983

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000389

Gnomad4 FIN exome

AF:

0.0000494

Gnomad4 NFE exome

AF:

0.000513

Gnomad4 OTH exome

AF:

0.000544

GnomAD4 genome

AF:

0.000483

AC:

AN:

111886

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

34044

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.000286

Gnomad4 ASJ

AF:

0.00113

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000790

Gnomad4 OTH

AF:

0.00132

Alfa

AF:

0.000830

Hom.:

Bravo

AF:

0.000536

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

ACSL4-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2017

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

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.47

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;.

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.060

MetaRNN

Benign

0.075

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.25

Sift

Benign

0.097

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.99

D;D;.

Vest4

0.23

MVP

0.41

MPC

1.6

ClinPred

0.041

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.86

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