rs372250472

Variant names:

• chrX-109682880-T-A
• rs372250472
• NM_001318510.2:c.245A>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001318510.2(ACSL4):​c.245A>T​(p.Tyr82Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,208,731 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00010 (0 hom. 34 hem.)
• Consequence: ACSL4 NM_001318510.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.01

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 -12 ACMG points.

• BP6: Variant X-109682880-T-A is Benign according to our data. Variant chrX-109682880-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 210087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSL4	NM_001318510.2	c.245A>T	p.Tyr82Phe	missense_variant	Exon 4 of 16	ENST00000672401.1	NP_001305439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSL4	ENST00000672401.1	c.245A>T	p.Tyr82Phe	missense_variant	Exon 4 of 16		NM_001318510.2	ENSP00000500273.1

Frequencies

GnomAD3 genomes AF: 0.0000802 AC: 9 AN: 112248 Hom.: 0 Cov.: 22 AF XY: 0.0000872 AC XY: 3 AN XY: 34386

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000150

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.0000492 AC: 9 AN: 182939 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67507

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000981

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 113 AN: 1096483 Hom.: 0 Cov.: 30 AF XY: 0.0000940 AC XY: 34 AN XY: 361879

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000802 AC: 9 AN: 112248 Hom.: 0 Cov.: 22 AF XY: 0.0000872 AC XY: 3 AN XY: 34386

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.000664

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 06, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Aug 02, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T;.;.;.;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.045	D;D;D;D;D;D;D
Sift4G	Benign	0.064	T;T;T;.;D;D;.
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.55
MVP		0.76
MPC		1.5
ClinPred		0.27	T
GERP RS		5.7
Varity_R		0.73
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs372250472; hg19: chrX-108926109;