chr17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000382.3(ALDH3A2):c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC(p.Arg9AlafsTer36) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000315 in 1,586,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
ALDH3A2
NM_000382.3 frameshift
NM_000382.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.41
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 72 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G is Pathogenic according to our data. Variant chr17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G is described in Lovd as [Pathogenic]. Variant chr17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000279 AC: 4AN: 1433802Hom.: 0 AF XY: 0.00000281 AC XY: 2AN XY: 710592
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GnomAD4 genome 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74348
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sjögren-Larsson syndrome Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 27, 2016 | - - |
| Pathogenic, no assertion criteria provided | research | Rizzo Lab, University of Nebraska Medical Center | Jun 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 16, 2019 | Variant summary: ALDH3A2 c.25_50del26 (p.Arg9AlafsX36) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 194754 control chromosomes (gnomAD). c.25_50del26 has been reported in the literature in individuals affected with Sjogren-Larsson Syndrome (Willemsen_2001, Sanders_2008, Kariminejad_2017). These data indicate that the variant may be associated with disease. Sanders_2008 reports this variant has an impact on protein function and results in decreasing activity from patients fibroblast cells. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 21, 2024 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2023 | This sequence change creates a premature translational stop signal (p.Arg9Alafs*36) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Sjögren-Larsson syndrome (PMID: 11408337, 29183715). It has also been observed to segregate with disease in related individuals. This variant is also known as c.21-46del. ClinVar contains an entry for this variant (Variation ID: 371103). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at