chr17-19648973-T-A
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000382.3(ALDH3A2):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,586,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 start_lost
NM_000382.3 start_lost
Scores
5
7
4
Clinical Significance
Conservation
PhyloP100: 1.87
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 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000382.3 (ALDH3A2) was described as [Likely_pathogenic] in ClinVar as 552722
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-19648973-T-A is Pathogenic according to our data. Variant chr17-19648973-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552666.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.2T>A | p.Met1? | start_lost | 1/10 | ENST00000176643.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH3A2 | ENST00000176643.11 | c.2T>A | p.Met1? | start_lost | 1/10 | 1 | NM_000382.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000497 AC: 1AN: 201014Hom.: 0 AF XY: 0.00000919 AC XY: 1AN XY: 108800
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GnomAD4 exome AF: 0.00000279 AC: 4AN: 1434610Hom.: 0 Cov.: 30 AF XY: 0.00000422 AC XY: 3AN XY: 711102
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sjögren-Larsson syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 26, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 07, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ALDH3A2 protein in which other variant(s) (p.Leu27Pro) have been determined to be pathogenic (PMID: 11408337). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 552666). This variant has not been reported in the literature in individuals affected with ALDH3A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ALDH3A2 mRNA. The next in-frame methionine is located at codon 33. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
.;T;.;.;T;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;D;.;.;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PROVEAN
Benign
N;.;.;.;N;.;N;N;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;D;.;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
0.99, 0.99
.;.;.;.;D;D;D;D;D
Vest4
0.68, 0.80, 0.81, 0.70, 0.86, 0.83, 0.86
MutPred
Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at