rs193072191

Variant names:

• chrX-109659521-C-T
• rs193072191
• NM_001318510.2:c.1698-10G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001318510.2(ACSL4):​c.1698-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,157,839 control chromosomes in the GnomAD database, including 10 homozygotes. There are 307 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 0.0055 (6 hom., 171 hem., cov: 23)
  • Exomes 𝑓: 0.00058 (4 hom. 136 hem.)
• Consequence: ACSL4 NM_001318510.2 intron
• Scores: Splicing: ADA: 0.00005922
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.33

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-109659521-C-T is Benign according to our data. Variant chrX-109659521-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00553 (615/111112) while in subpopulation AFR AF= 0.0172 (527/30647). AF 95% confidence interval is 0.016. There are 6 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSL4	NM_001318510.2	c.1698-10G>A		intron_variant	Intron 14 of 15	ENST00000672401.1	NP_001305439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSL4	ENST00000672401.1	c.1698-10G>A		intron_variant	Intron 14 of 15		NM_001318510.2	ENSP00000500273.1

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 597 AN: 111063 Hom.: 3 Cov.: 23 AF XY: 0.00488 AC XY: 163 AN XY: 33421

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00612

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000562

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00403

GnomAD3 exomes AF: 0.00149 AC: 270 AN: 180881 Hom.: 2 AF XY: 0.00101 AC XY: 67 AN XY: 66027

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000214

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000585 AC: 612 AN: 1046727 Hom.: 4 Cov.: 24 AF XY: 0.000425 AC XY: 136 AN XY: 319693

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000246

Gnomad4 FIN exome AF: 0.0000250

Gnomad4 NFE exome AF: 0.00000377

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00553 AC: 615 AN: 111112 Hom.: 6 Cov.: 23 AF XY: 0.00511 AC XY: 171 AN XY: 33480

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.00611

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000564

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00286 Hom.: 15

Bravo AF: 0.00682

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-syndromic X-linked intellectual disability Uncertain:1

Aug 31, 2011

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 17, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACSL4-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000059
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs193072191; hg19: chrX-108902750;