NM_001318510.2:c.1585_1586delCGinsTC

Variant names:

• chrX-109661642-CG-GA
• NM_001318510.2:c.1585_1586delCGinsTC
• ACSL4 p.Arg529Ser

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_001318510.2(ACSL4):​c.1585_1586delCGinsTC​(p.Arg529Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R529H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ACSL4 NM_001318510.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Illumina, ClinGen, Orphanet
• intellectual disability, X-linked 63

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-109661642-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 633031.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	NM_001318510.2	MANE Select	c.1585_1586delCGinsTC	p.Arg529Ser	missense splice_region	N/A	NP_001305439.1	O60488-2
	ACSL4	NM_001318509.2		c.1708_1709delCGinsTC	p.Arg570Ser	missense splice_region	N/A	NP_001305438.1	O60488-1
	ACSL4	NM_001437245.1		c.1708_1709delCGinsTC	p.Arg570Ser	missense splice_region	N/A	NP_001424174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	ENST00000672401.1	MANE Select	c.1585_1586delCGinsTC	p.Arg529Ser	missense splice_region	N/A	ENSP00000500273.1	O60488-2
	ACSL4	ENST00000348502.10	TSL:1	c.1585_1586delCGinsTC	p.Arg529Ser	missense splice_region	N/A	ENSP00000262835.7	O60488-2
	ACSL4	ENST00000340800.7	TSL:5	c.1708_1709delCGinsTC	p.Arg570Ser	missense splice_region	N/A	ENSP00000339787.2	O60488-1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-108904871;