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]

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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 testingInvitaeApr 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