17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000176643.11(ALDH3A2):c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC(p.Arg9AlafsTer36) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000315 in 1,586,004 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R9R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
ALDH3A2
ENST00000176643.11 frameshift
ENST00000176643.11 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.41
Publications
1 publications found
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 syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 140 pathogenic variants in the truncated region.
PP5
Variant 17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G is Pathogenic according to our data. Variant chr17-19648991-GGGTCCGACAGGCGTTCCTGTCCGGCC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 371103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000176643.11. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ALDH3A2 | NM_000382.3 | MANE Select | c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC | p.Arg9AlafsTer36 | frameshift | Exon 1 of 10 | NP_000373.1 | ||
| ALDH3A2 | NM_001031806.2 | c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC | p.Arg9AlafsTer36 | frameshift | Exon 1 of 11 | NP_001026976.1 | |||
| ALDH3A2 | NM_001369136.1 | c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC | p.Arg9AlafsTer36 | frameshift | Exon 2 of 12 | NP_001356065.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ALDH3A2 | ENST00000176643.11 | TSL:1 MANE Select | c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC | p.Arg9AlafsTer36 | frameshift | Exon 1 of 10 | ENSP00000176643.6 | ||
| ALDH3A2 | ENST00000339618.8 | TSL:1 | c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC | p.Arg9AlafsTer36 | frameshift | Exon 1 of 11 | ENSP00000345774.4 | ||
| ALDH3A2 | ENST00000671878.1 | c.25_50delCGACAGGCGTTCCTGTCCGGCCGGTC | p.Arg9AlafsTer36 | frameshift | Exon 1 of 10 | ENSP00000500516.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152202
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000279 AC: 4AN: 1433802Hom.: 0 AF XY: 0.00000281 AC XY: 2AN XY: 710592 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4
AN:
1433802
Hom.:
AF XY:
AC XY:
2
AN XY:
710592
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33206
American (AMR)
AF:
AC:
0
AN:
40200
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25376
East Asian (EAS)
AF:
AC:
0
AN:
38740
South Asian (SAS)
AF:
AC:
0
AN:
82358
European-Finnish (FIN)
AF:
AC:
0
AN:
50172
Middle Eastern (MID)
AF:
AC:
0
AN:
5404
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1099094
Other (OTH)
AF:
AC:
1
AN:
59252
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000266003), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.388
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 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74348 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
152202
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74348
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
1
AN:
41450
American (AMR)
AF:
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5190
South Asian (SAS)
AF:
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68036
Other (OTH)
AF:
AC:
0
AN:
2094
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
5
-
-
Sjögren-Larsson syndrome (5)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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