rs797045216

Variant names:

• chrX-109661650-TAA-T
• rs797045216
• NM_001318510.2:c.1583-7_1583-6delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001318510.2(ACSL4):​c.1583-7_1583-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000978 in 1,022,713 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.8e-7 (0 hom. 0 hem.)
• Consequence: ACSL4 NM_001318510.2 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1583-7_1583-6delTT		splice_region intron	N/A	NP_001305439.1	O60488-2
	ACSL4	NM_001318509.2		c.1706-7_1706-6delTT		splice_region intron	N/A	NP_001305438.1	O60488-1
	ACSL4	NM_001437245.1		c.1706-7_1706-6delTT		splice_region intron	N/A	NP_001424174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	ENST00000672401.1	MANE Select	c.1583-7_1583-6delTT		splice_region intron	N/A	ENSP00000500273.1	O60488-2
	ACSL4	ENST00000348502.10	TSL:1	c.1583-7_1583-6delTT		splice_region intron	N/A	ENSP00000262835.7	O60488-2
	ACSL4	ENST00000340800.7	TSL:5	c.1706-7_1706-6delTT		splice_region intron	N/A	ENSP00000339787.2	O60488-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000548 AC: 1 AN: 182335 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.78e-7 AC: 1 AN: 1022713 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 303011

African (AFR) AF: 0.00 AC: 0 AN: 25052

American (AMR) AF: 0.00 AC: 0 AN: 35014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18871

East Asian (EAS) AF: 0.00 AC: 0 AN: 29801

South Asian (SAS) AF: 0.00 AC: 0 AN: 52448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3913

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 773589

Other (OTH) AF: 0.0000229 AC: 1 AN: 43576

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs797045216; hg19: chrX-108904879;