NM_000382.3:c.798+5G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000382.3(ALDH3A2):​c.798+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,429,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALDH3A2
NM_000382.3 splice_region, intron

Scores

2
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.86

Publications

1 publications found
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]
ALDH3A2 Gene-Disease associations (from GenCC):
  • Sjogren-Larsson syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-19657867-G-A is Pathogenic according to our data. Variant chr17-19657867-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189079.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALDH3A2NM_000382.3 linkc.798+5G>A splice_region_variant, intron_variant Intron 5 of 9 ENST00000176643.11 NP_000373.1 P51648-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALDH3A2ENST00000176643.11 linkc.798+5G>A splice_region_variant, intron_variant Intron 5 of 9 1 NM_000382.3 ENSP00000176643.6 P51648-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000210
AC:
3
AN:
1429856
Hom.:
0
Cov.:
28
AF XY:
0.00000280
AC XY:
2
AN XY:
713284
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32778
American (AMR)
AF:
0.00
AC:
0
AN:
44654
Ashkenazi Jewish (ASJ)
AF:
0.0000386
AC:
1
AN:
25910
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39522
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85530
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53334
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5720
European-Non Finnish (NFE)
AF:
0.00000185
AC:
2
AN:
1083046
Other (OTH)
AF:
0.00
AC:
0
AN:
59362
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.342
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:2
-
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Dec 09, 2014
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1
Oct 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in two abnormal transcripts (PMID: 10577908). ClinVar contains an entry for this variant (Variation ID: 189079). This variant has been observed in individual(s) with Sjögren-Larsson syndrome (PMID: 10577908). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the ALDH3A2 gene. It does not directly change the encoded amino acid sequence of the ALDH3A2 protein. It affects a nucleotide within the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.56
CADD
Benign
22
DANN
Benign
0.84
PhyloP100
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=3/97
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.96
SpliceAI score (max)
0.89
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.89
Position offset: -5

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

Publications

Other links and lift over

dbSNP: rs786204677; hg19: chr17-19561180; API