17-19740351-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000691.5(ALDH3A1):​c.934G>A​(p.Ala312Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ALDH3A1
NM_000691.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.533
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.064251274).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALDH3A1NM_000691.5 linkuse as main transcriptc.934G>A p.Ala312Thr missense_variant 7/11 ENST00000225740.11 NP_000682.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALDH3A1ENST00000225740.11 linkuse as main transcriptc.934G>A p.Ala312Thr missense_variant 7/111 NM_000691.5 ENSP00000225740 P1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250908
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135682
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461576
Hom.:
0
Cov.:
30
AF XY:
0.00000825
AC XY:
6
AN XY:
727094
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.0000671
AC XY:
5
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

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 submitterclinical testingAmbry GeneticsAug 30, 2021The c.934G>A (p.A312T) alteration is located in exon 6 (coding exon 6) of the ALDH3A1 gene. This alteration results from a G to A substitution at nucleotide position 934, causing the alanine (A) at amino acid position 312 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
10
DANN
Benign
0.97
DEOGEN2
Benign
0.11
T;T;T;T;T
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.89
FATHMM_MKL
Benign
0.15
N
LIST_S2
Uncertain
0.86
D;.;T;.;T
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.064
T;T;T;T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
0.73
.;N;N;N;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.5
.;N;N;N;N
REVEL
Benign
0.077
Sift
Benign
0.14
.;T;T;T;T
Sift4G
Benign
0.45
T;T;T;T;T
Polyphen
0.0050
.;B;B;B;.
Vest4
0.13
MVP
0.75
MPC
0.22
ClinPred
0.044
T
GERP RS
1.6
Varity_R
0.14
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs201594817; hg19: chr17-19643664; COSMIC: COSV56734987; COSMIC: COSV56734987; API