rs192665139

chrX-109663409-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001318510.2(ACSL4):c.1391-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,195,951 control chromosomes in the GnomAD database, including 3 homozygotes. There are 207 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 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 0.0034 (3 hom., 102 hem., cov: 23)
  • Exomes 𝑓: 0.00037 (0 hom. 105 hem.)
• Consequence: ACSL4 NM_001318510.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001197
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.808

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-109663409-A-G is Benign according to our data. Variant chrX-109663409-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495142.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSL4	NM_001318510.2	c.1391-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000672401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSL4	ENST00000672401.1	c.1391-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001318510.2	P4

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 376 AN: 112385 Hom.: 3 Cov.: 23 AF XY: 0.00286 AC XY: 99 AN XY: 34575

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.000917 AC: 166 AN: 181080 Hom.: 0 AF XY: 0.000408 AC XY: 27 AN XY: 66242

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000258

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000161

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000248

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000374 AC: 405 AN: 1083512 Hom.: 0 Cov.: 27 AF XY: 0.000300 AC XY: 105 AN XY: 349664

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000371

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000603

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.00339 AC: 381 AN: 112439 Hom.: 3 Cov.: 23 AF XY: 0.00294 AC XY: 102 AN XY: 34639

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.00123

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.00161 Hom.: 6

Bravo AF: 0.00389

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-syndromic X-linked intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 18, 2013

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 03, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.3
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0080
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: rs192665139; hg19: chrX-108906638;