17-19741197-C-T

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

Scores

11
7
1

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.49
Variant links:
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]

Genome browser will be placed here

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
ALDH3A1NM_000691.5 linkuse as main transcriptc.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
ALDH3A1ENST00000225740.11 linkuse as main transcriptc.703G>A p.Gly235Arg missense_variant 6/111 NM_000691.5 ENSP00000225740 P1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000636
AC:
16
AN:
251414
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000815
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000328
AC:
48
AN:
1461598
Hom.:
0
Cov.:
32
AF XY:
0.0000316
AC XY:
23
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000302
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

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 providedcase-controlRefractive Surgery Department, Bright Eye HospitalFeb 25, 2023ALDH3A1 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.59
.;D;D;D;D;D;D
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D;D;.;D;.;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.4
.;.;H;H;H;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-6.6
D;.;D;D;D;D;.
REVEL
Pathogenic
0.92
Sift
Uncertain
0.020
D;.;D;D;D;D;.
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;D;.;.
Vest4
0.90
MutPred
0.88
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
0.92
MPC
0.90
ClinPred
0.93
D
GERP RS
4.5
Varity_R
0.97
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs761232139; hg19: chr17-19644510; API