17-19741197-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000691.5(ALDH3A1):c.703G>A(p.Gly235Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,786 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 (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
ALDH3A1
NM_000691.5 missense
NM_000691.5 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 7.49
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922
PP5
Variant 17-19741197-C-T is Pathogenic according to our data. Variant chr17-19741197-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2442791.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH3A1 | NM_000691.5 | c.703G>A | p.Gly235Arg | missense_variant | 6/11 | ENST00000225740.11 | NP_000682.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALDH3A1 | ENST00000225740.11 | c.703G>A | p.Gly235Arg | missense_variant | 6/11 | 1 | NM_000691.5 | ENSP00000225740 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251414Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135868
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GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461598Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727102
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74342
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Keratoconus Pathogenic:1
Likely pathogenic, no assertion criteria provided | case-control | Refractive Surgery Department, Bright Eye Hospital | Feb 25, 2023 | ALDH3A1 is thought to be involved in KC etiology.12-14 ALDH3A1 variants, rs1042183 and rs2228100, are strongly associated with KC in the Polish and Korean populations.12, 14 The association of ALDH3A1 with intraocular pressure15 and refractive astigmatism16, 17 have also been observed. Furthermore, the relationship between astigmatism and KC has been reported, as 14.1% of patients with more than 2D astigmatism suffer from KC.18 Our findings further demonstrated the association of ALDH3A1 with KC. A novel SNP in ALDH3A1 was detected, g.19644510G>A, (c.703G>A, p.Gly235Arg [rs761232139]), causing a p.G235R amino acid change. This variant is located in exon 6 of ALDH3A1 gene and is predicted as highly conserved among species and probably damaging. The variant was identified in all KC members from the family 2, which means that rs761232139 may be a risk factor for KC and inherited in a dominant model. The residue was considered as a distinct structural and/or functional sequence of ALDH3A1, which is adjacent to the active site Cys-243. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;D;D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;.;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;H;H;H;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;D;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0066);.;Gain of MoRF binding (P = 0.0066);Gain of MoRF binding (P = 0.0066);Gain of MoRF binding (P = 0.0066);Gain of MoRF binding (P = 0.0066);.;
MVP
MPC
0.90
ClinPred
D
GERP RS
Varity_R
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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