rs782158792
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000033.4(ABCD1):āc.1526A>Gā(p.Asn509Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,209,600 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N509K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000033.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.1526A>G | p.Asn509Ser | missense_variant | 6/10 | ENST00000218104.6 | |
LOC124905226 | XR_007068350.1 | n.1419T>C | non_coding_transcript_exon_variant | 1/2 | |||
ABCD1 | XM_047441916.1 | c.1826A>G | p.Asn609Ser | missense_variant | 7/11 | ||
ABCD1 | XM_047441917.1 | c.1582A>G | p.Met528Val | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.1526A>G | p.Asn509Ser | missense_variant | 6/10 | 1 | NM_000033.4 | P1 | |
PLXNB3-AS1 | ENST00000434284.1 | n.72-1551T>C | intron_variant, non_coding_transcript_variant | 3 | |||||
ABCD1 | ENST00000443684.2 | n.529A>G | non_coding_transcript_exon_variant | 5/6 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000177 AC: 2AN: 112737Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 34919
GnomAD3 exomes AF: 0.00000549 AC: 1AN: 182301Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 66881
GnomAD4 exome AF: 0.00000547 AC: 6AN: 1096863Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1AN XY: 362357
GnomAD4 genome ? AF: 0.0000177 AC: 2AN: 112737Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 34919
ClinVar
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 07, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 509 of the ABCD1 protein (p.Asn509Ser). This variant is present in population databases (rs782158792, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of adrenoleukodystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 458633). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn509 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 14767898, 16415970), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 10, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2017 | The p.N509S variant (also known as c.1526A>G), located in coding exon 6 of the ABCD1 gene, results from an A to G substitution at nucleotide position 1526. The asparagine at codon 509 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at