rs200451158

Variant names:

• chrX-109665485-T-C
• rs200451158
• NM_001318510.2:c.1325A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.28
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 194058.
• BS2: High Hemizygotes in GnomAd4 at 16 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318510.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	NM_001318510.2	MANE Select	c.1325A>G	p.Tyr442Cys	missense	Exon 12 of 16	NP_001305439.1
	ACSL4	NM_001318509.2		c.1448A>G	p.Tyr483Cys	missense	Exon 12 of 16	NP_001305438.1
	ACSL4	NM_001437245.1		c.1448A>G	p.Tyr483Cys	missense	Exon 12 of 16	NP_001424174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	ENST00000672401.1	MANE Select	c.1325A>G	p.Tyr442Cys	missense	Exon 12 of 16	ENSP00000500273.1
	ACSL4	ENST00000348502.10	TSL:1	c.1325A>G	p.Tyr442Cys	missense	Exon 12 of 16	ENSP00000262835.7
	ACSL4	ENST00000340800.7	TSL:5	c.1448A>G	p.Tyr483Cys	missense	Exon 13 of 17	ENSP00000339787.2

Frequencies

GnomAD3 genomes AF: 0.000483 AC: 54 AN: 111886 Hom.: 1 Cov.: 23

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

GnomAD2 exomes AF: 0.000458 AC: 84 AN: 183308 AF XY: 0.000590

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 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.: 1 Cov.: 28 AF XY: 0.000527 AC XY: 189 AN XY: 358968

African (AFR) AF: 0.000152 AC: 4 AN: 26295

American (AMR) AF: 0.000170 AC: 6 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.000983 AC: 19 AN: 19327

East Asian (EAS) AF: 0.00 AC: 0 AN: 30129

South Asian (SAS) AF: 0.000389 AC: 21 AN: 54027

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40502

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4123

European-Non Finnish (NFE) AF: 0.000513 AC: 430 AN: 837831

Other (OTH) AF: 0.000544 AC: 25 AN: 45920

GnomAD4 genome AF: 0.000483 AC: 54 AN: 111886 Hom.: 1 Cov.: 23 AF XY: 0.000470 AC XY: 16 AN XY: 34044

African (AFR) AF: 0.000130 AC: 4 AN: 30811

American (AMR) AF: 0.000286 AC: 3 AN: 10503

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000790 AC: 42 AN: 53145

Other (OTH) AF: 0.00132 AC: 2 AN: 1512

Alfa AF: 0.000773 Hom.: 38

Bravo AF: 0.000536

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.00136

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	ACSL4-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.25
Sift	Benign	0.097	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.23
MVP		0.41
MPC		1.6
ClinPred		0.041	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.86
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs200451158; hg19: chrX-108908714;