rs1036733598

Positions:

• chr17-19664947-G-C
• chr17-19664947-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000176643.11(ALDH3A2):​c.1108-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALDH3A2 ENST00000176643.11 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-19664947-G-C is Pathogenic according to our data. Variant chr17-19664947-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 370452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19664947-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH3A2	NM_000382.3	c.1108-1G>C		splice_acceptor_variant		ENST00000176643.11	NP_000373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH3A2	ENST00000176643.11	c.1108-1G>C		splice_acceptor_variant		1	NM_000382.3	ENSP00000176643	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251256 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.85e-7 AC: 1 AN: 1460504 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2020	Variant summary: ALDH3A2 c.1108-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' acceptor site. A publication also reported experimental evidence confirming that this variant affects mRNA splicing, resulting in exon skipping (Rizzo_1999). The variant allele was found at a frequency of 4e-06 in 251256 control chromosomes. c.1108-1G>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Sjogren-Larsson Syndrome (Rizzo_1999, Carney_2004, Auada_2006). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated <10% of normal activity in fibroblasts derived from homozygous patients (Carney_2004, Auada_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2023	This sequence change affects an acceptor splice site in intron 7 of the ALDH3A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with Sjogren-Larsson syndrome (PMID: 10577908, 15241804). ClinVar contains an entry for this variant (Variation ID: 370452). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2023	Canonical splice site variant shown to result in a null allele by splicing studies in a gene for which loss-of-function is a known mechanism of disease (Rizzo et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29742247, 16927642, 10577908, 34426522, 29899769, 15241804, 31589614, 25525159, 16536828) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1036733598; hg19: chr17-19568260;