rs183171123

Variant names:

• chrX-109678262-T-C
• rs183171123
• NM_001318510.2:c.806+3A>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.806+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,210,205 control chromosomes in the GnomAD database, including 2 homozygotes. There are 582 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., 26 hem., cov: 23)
  • Exomes 𝑓: 0.0016 (2 hom. 556 hem.)
• Consequence: ACSL4 NM_001318510.2 splice_region, intron
• Scores: Splicing: ADA: 0.2819
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.45
• 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: 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 (BayesDel_noAF=-0.36).
• BP6: Variant X-109678262-T-C is Benign according to our data. Variant chrX-109678262-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198513.
• BS2: High Hemizygotes in GnomAd4 at 26 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.806+3A>G		splice_region intron	N/A	NP_001305439.1
	ACSL4	NM_001318509.2		c.929+3A>G		splice_region intron	N/A	NP_001305438.1
	ACSL4	NM_001437245.1		c.929+3A>G		splice_region intron	N/A	NP_001424174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	ENST00000672401.1	MANE Select	c.806+3A>G		splice_region intron	N/A	ENSP00000500273.1
	ACSL4	ENST00000348502.10	TSL:1	c.806+3A>G		splice_region intron	N/A	ENSP00000262835.7
	ACSL4	ENST00000340800.7	TSL:5	c.929+3A>G		splice_region intron	N/A	ENSP00000339787.2

Frequencies

GnomAD3 genomes AF: 0.000936 AC: 105 AN: 112163 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000493

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000664

GnomAD2 exomes AF: 0.000725 AC: 133 AN: 183400 AF XY: 0.000604

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000437

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00161 AC: 1770 AN: 1097988 Hom.: 2 Cov.: 31 AF XY: 0.00153 AC XY: 556 AN XY: 363354

African (AFR) AF: 0.000189 AC: 5 AN: 26399

American (AMR) AF: 0.0000568 AC: 2 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54144

European-Finnish (FIN) AF: 0.000222 AC: 9 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00200 AC: 1688 AN: 841925

Other (OTH) AF: 0.00139 AC: 64 AN: 46088

GnomAD4 genome AF: 0.000936 AC: 105 AN: 112217 Hom.: 0 Cov.: 23 AF XY: 0.000756 AC XY: 26 AN XY: 34377

African (AFR) AF: 0.000194 AC: 6 AN: 30929

American (AMR) AF: 0.000283 AC: 3 AN: 10602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.000493 AC: 3 AN: 6082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00173 AC: 92 AN: 53250

Other (OTH) AF: 0.000656 AC: 1 AN: 1524

Alfa AF: 0.00102 Hom.: 9

Bravo AF: 0.000960

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.91
PhyloP100		2.4
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.28
dbscSNV1_RF	Benign	0.54
SpliceAI score (max)		0.030		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: rs183171123; hg19: chrX-108921491;