rs387906257
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000382.3(ALDH3A2):c.1307_1311dup(p.Leu438ThrfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
ALDH3A2
NM_000382.3 frameshift
NM_000382.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.93
Genes affected
ALDH3A2 (HGNC:403): (aldehyde dehydrogenase 3 family member A2) Aldehyde dehydrogenase isozymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This gene product catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid. Mutations in the gene cause Sjogren-Larsson syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-19671818-T-TAACAA is Pathogenic according to our data. Variant chr17-19671818-T-TAACAA is described in ClinVar as [Pathogenic]. Clinvar id is 1642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH3A2 | NM_000382.3 | c.1307_1311dup | p.Leu438ThrfsTer21 | frameshift_variant | 9/10 | ENST00000176643.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH3A2 | ENST00000176643.11 | c.1307_1311dup | p.Leu438ThrfsTer21 | frameshift_variant | 9/10 | 1 | NM_000382.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727242
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sjögren-Larsson syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 05, 2018 | - - |
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 10, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2022 | ClinVar contains an entry for this variant (Variation ID: 1642). This variant is also known as 1311insACAAA. This premature translational stop signal has been observed in individual(s) with Sjogren-Larsson syndrome (PMID: 9250352). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu438Thrfs*21) in the ALDH3A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at