X-109661643-G-T

Variant names:

• chrX-109661643-G-T
• rs122458138
• NM_001318510.2:c.1585C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001318510.2(ACSL4):​c.1585C>A​(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. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). 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)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ACSL4 NM_001318510.2 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 7 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-109661643-G-T is Pathogenic according to our data. Variant chrX-109661643-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11564.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1585C>A	p.Arg529Ser	missense splice_region	Exon 14 of 16	NP_001305439.1
	ACSL4	NM_001318509.2		c.1708C>A	p.Arg570Ser	missense splice_region	Exon 14 of 16	NP_001305438.1
	ACSL4	NM_001437245.1		c.1708C>A	p.Arg570Ser	missense splice_region	Exon 14 of 16	NP_001424174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	ENST00000672401.1	MANE Select	c.1585C>A	p.Arg529Ser	missense splice_region	Exon 14 of 16	ENSP00000500273.1
	ACSL4	ENST00000348502.10	TSL:1	c.1585C>A	p.Arg529Ser	missense splice_region	Exon 14 of 16	ENSP00000262835.7
	ACSL4	ENST00000340800.7	TSL:5	c.1708C>A	p.Arg570Ser	missense splice_region	Exon 15 of 17	ENSP00000339787.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1034433 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 310377

African (AFR) AF: 0.00 AC: 0 AN: 25217

American (AMR) AF: 0.00 AC: 0 AN: 35038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18931

East Asian (EAS) AF: 0.00 AC: 0 AN: 29864

South Asian (SAS) AF: 0.00 AC: 0 AN: 52655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3948

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 784366

Other (OTH) AF: 0.00 AC: 0 AN: 43964

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 63 Pathogenic:1

Apr 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Loss of stability (P = 0.1127)
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -2

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

Other links and lift over

dbSNP: rs122458138; hg19: chrX-108904872;