rs72547569
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000382.3(ALDH3A2):c.798G>C(p.Lys266Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,439,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000382.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH3A2 | NM_000382.3 | c.798G>C | p.Lys266Asn | missense_variant, splice_region_variant | 5/10 | ENST00000176643.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH3A2 | ENST00000176643.11 | c.798G>C | p.Lys266Asn | missense_variant, splice_region_variant | 5/10 | 1 | NM_000382.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 152130Hom.: 0 Cov.: 33 FAILED QC
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250684Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135542
GnomAD4 exome AF: 0.0000174 AC: 25AN: 1439728Hom.: 0 Cov.: 29 AF XY: 0.0000195 AC XY: 14AN XY: 717754
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that this missense change alters ALDH3A2 gene expression (PMID: 10577908). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1643). This missense change has been observed in individuals with Sjögren-Larsson syndrome (PMID: 11408337, 17971613). This variant is present in population databases (rs72547569, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 266 of the ALDH3A2 protein (p.Lys266Asn). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2016 | The K266N variant in the ALDH3A2 gene has been reported previously in patients with Sjogren-Larsson syndrome (SLS) (Rizzo et al., 1999; Willemsen et al., 2001). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K266N is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, several splice prediction models predict that this variant destroys the natural splice donor site in intron 5. Therefore, the K266N variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Sjögren-Larsson syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at