rs1556225792
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001318510.2(ACSL4):c.1561G>A(p.Asp521Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,093,550 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )
Consequence
ACSL4
NM_001318510.2 missense
NM_001318510.2 missense
Scores
6
4
6
Clinical Significance
Conservation
PhyloP100: 6.17
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.904
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACSL4 | NM_001318510.2 | c.1561G>A | p.Asp521Asn | missense_variant | 13/16 | ENST00000672401.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACSL4 | ENST00000672401.1 | c.1561G>A | p.Asp521Asn | missense_variant | 13/16 | NM_001318510.2 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome AF: 0.00000274 AC: 3AN: 1093550Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1AN XY: 359526
GnomAD4 exome
AF:
AC:
3
AN:
1093550
Hom.:
Cov.:
29
AF XY:
AC XY:
1
AN XY:
359526
Gnomad4 AFR exome
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Gnomad4 SAS exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 63 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2014 | The c.1561G>A (p.D521N) alteration is located in exon 13 (coding exon 11) of the ACSL4 gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the aspartic acid (D) at amino acid position 521 to be replaced by an asparagine (N). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the ACSL4/FACL4 c.1561G>A alteration was not observed among 6,780 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. This amino acid position is completely conserved on sequence alignment in available vertibrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.521D amino acid is located in the AMP-dependent synthetase/ligase domain of the protein. The alteration is predicted deleterious by in silico models:_x000D_ The p.D521N alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;.
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Loss of catalytic residue at D562 (P = 0.1254);Loss of catalytic residue at D562 (P = 0.1254);.;
MVP
MPC
1.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at