17-19739031-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000691.5(ALDH3A1):āc.1181A>Gā(p.His394Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,818 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
ALDH3A1
NM_000691.5 missense
NM_000691.5 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 6.00
Genes affected
ALDH3A1 (HGNC:405): (aldehyde dehydrogenase 3 family member A1) Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-derived acetaldehyde and in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. The enzyme encoded by this gene forms a cytoplasmic homodimer that preferentially oxidizes aromatic and medium-chain (6 carbons or more) saturated and unsaturated aldehyde substrates. It is thought to promote resistance to UV and 4-hydroxy-2-nonenal-induced oxidative damage in the cornea. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH3A1 | NM_000691.5 | c.1181A>G | p.His394Arg | missense_variant | 9/11 | ENST00000225740.11 | NP_000682.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALDH3A1 | ENST00000225740.11 | c.1181A>G | p.His394Arg | missense_variant | 9/11 | 1 | NM_000691.5 | ENSP00000225740 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461666Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727156
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2023 | The c.1181A>G (p.H394R) alteration is located in exon 8 (coding exon 8) of the ALDH3A1 gene. This alteration results from a A to G substitution at nucleotide position 1181, causing the histidine (H) at amino acid position 394 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;M;M;M
MutationTaster
Benign
D;D;D;D;N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D;D
REVEL
Pathogenic
Sift
Benign
T;.;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
1.0
.;.;D;D;D
Vest4
MutPred
0.81
.;.;Loss of catalytic residue at H394 (P = 0.1026);Loss of catalytic residue at H394 (P = 0.1026);Loss of catalytic residue at H394 (P = 0.1026);
MVP
MPC
0.91
ClinPred
D
GERP RS
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