chrX-109643871-C-T

Variant names:

• chrX-109643871-C-T
• rs10126612
• NM_001318510.2:c.*158G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001318510.2(ACSL4):​c.*158G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00992 in 614,092 control chromosomes in the GnomAD database, including 68 homozygotes. There are 1,996 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., 500 hem., cov: 23)
  • Exomes 𝑓: 0.0089 (44 hom. 1496 hem.)
• Consequence: ACSL4 NM_001318510.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.232
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0147 (1648/111948) while in subpopulation EAS AF = 0.0555 (199/3587). AF 95% confidence interval is 0.0492. There are 24 homozygotes in GnomAd4. There are 500 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	NM_001318510.2	MANE Select	c.*158G>A		3_prime_UTR	Exon 16 of 16	NP_001305439.1	O60488-2
	ACSL4	NM_001318509.2		c.*158G>A		3_prime_UTR	Exon 16 of 16	NP_001305438.1	O60488-1
	ACSL4	NM_001437245.1		c.*158G>A		3_prime_UTR	Exon 16 of 16	NP_001424174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL4	ENST00000672401.1	MANE Select	c.*158G>A		3_prime_UTR	Exon 16 of 16	ENSP00000500273.1	O60488-2
	ACSL4	ENST00000348502.10	TSL:1	c.*158G>A		3_prime_UTR	Exon 16 of 16	ENSP00000262835.7	O60488-2
	ACSL4	ENST00000340800.7	TSL:5	c.*158G>A		3_prime_UTR	Exon 17 of 17	ENSP00000339787.2	O60488-1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 1642 AN: 111892 Hom.: 24 Cov.: 23

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.0258

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.00369

Gnomad OTH AF: 0.0127

GnomAD4 exome AF: 0.00885 AC: 4446 AN: 502144 Hom.: 44 Cov.: 8 AF XY: 0.0104 AC XY: 1496 AN XY: 144462

African (AFR) AF: 0.0307 AC: 421 AN: 13729

American (AMR) AF: 0.0236 AC: 555 AN: 23489

Ashkenazi Jewish (ASJ) AF: 0.000150 AC: 2 AN: 13315

East Asian (EAS) AF: 0.0436 AC: 1057 AN: 24255

South Asian (SAS) AF: 0.0261 AC: 894 AN: 34271

European-Finnish (FIN) AF: 0.000190 AC: 5 AN: 26331

Middle Eastern (MID) AF: 0.00730 AC: 19 AN: 2604

European-Non Finnish (NFE) AF: 0.00359 AC: 1215 AN: 338343

Other (OTH) AF: 0.0108 AC: 278 AN: 25807

GnomAD4 genome AF: 0.0147 AC: 1648 AN: 111948 Hom.: 24 Cov.: 23 AF XY: 0.0146 AC XY: 500 AN XY: 34194

African (AFR) AF: 0.0328 AC: 1012 AN: 30842

American (AMR) AF: 0.0138 AC: 146 AN: 10561

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2650

East Asian (EAS) AF: 0.0555 AC: 199 AN: 3587

South Asian (SAS) AF: 0.0266 AC: 72 AN: 2703

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6023

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.00369 AC: 196 AN: 53161

Other (OTH) AF: 0.0125 AC: 19 AN: 1520

Alfa AF: 0.00932 Hom.: 106

Bravo AF: 0.0161

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.82
DANN	Benign	0.45
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs10126612; hg19: chrX-108887100;