chr17-19648973-T-A

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

Scores

5
7
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.87
Variant links:
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]

Genome browser will be placed here

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
ALDH3A2NM_000382.3 linkuse as main transcriptc.2T>A p.Met1? start_lost 1/10 ENST00000176643.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALDH3A2ENST00000176643.11 linkuse as main transcriptc.2T>A p.Met1? start_lost 1/101 NM_000382.3 P1P51648-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000497
AC:
1
AN:
201014
Hom.:
0
AF XY:
0.00000919
AC XY:
1
AN XY:
108800
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000116
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000279
AC:
4
AN:
1434610
Hom.:
0
Cov.:
30
AF XY:
0.00000422
AC XY:
3
AN XY:
711102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000364
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 submitterclinical testingCounsylJun 26, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 07, 2023For 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
25
DANN
Benign
0.93
DEOGEN2
Benign
0.028
.;T;.;.;T;.;T;.;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
D;D;.;.;D;.;.;D;.
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.45
D
MutationTaster
Benign
1.0
D;D;D;D;D
PROVEAN
Benign
-1.6
N;.;.;.;N;.;N;N;.
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0020
D;.;.;.;D;.;D;D;.
Sift4G
Uncertain
0.0060
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
0.85
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
0.96
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.92
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs61737991; hg19: chr17-19552286; API