rs781059624

chr17-19671802-TAA-T

Variant summary

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

The NM_000382.3(ALDH3A2):c.1291_1292del(p.Lys431GlufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L430L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ALDH3A2 NM_000382.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.57

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-19671802-TAA-T is Pathogenic according to our data. Variant chr17-19671802-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 495850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19671802-TAA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH3A2	NM_000382.3	c.1291_1292del	p.Lys431GlufsTer5	frameshift_variant	9/10	ENST00000176643.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH3A2	ENST00000176643.11	c.1291_1292del	p.Lys431GlufsTer5	frameshift_variant	9/10	1	NM_000382.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2016	Variant summary: The ALDH3A2 c.1291_1292delAA (p.Lys431Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent ALDH3A2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121534 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDH3A2 variant (0.0017889). This variant has been reported in multiple SLS pts as homozygote or compound heterozygotes. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	Feb 11, 2019	The proband has another variant, NM_000382.2: c.1309A>T (p.Lys437*). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 21, 2018	The p.Lys431GlufsX5 variant in ALDH3A2 has been reported in the homozygous or co mpound heterozygous state in 2 Japanese individuals with Sjogren-Larsson syndrom e and segregated with disease in 1 affected family member (Rizzo 1999, Takeichi 2013 ). It has also been identified in 1/17248 of East Asian chromosomes by gnom AD (http://gnomad.broadinstitute.org). This variant has also been reported in Cl inVar (Variation ID 495850). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 431 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ALDH3A2 gene is an established disease mechanism in Sjogren-Larsson syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Sjogren-Larsson syndrome based on case observations, segregation studies, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PM2, PM 3, PP1. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2023

This sequence change creates a premature translational stop signal (p.Lys431Glufs*5) in the ALDH3A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). This variant is present in population databases (rs781059624, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Sjogren-Larsson syndrome (PMID: 10577908, 30157790). ClinVar contains an entry for this variant (Variation ID: 495850). 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. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs781059624; hg19: chr17-19575115;