17-19648999-C-T

Position:

• chr17-19648999-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000382.3(ALDH3A2):​c.28C>T​(p.Gln10Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,433,450 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ALDH3A2 NM_000382.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.770

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 11 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 161 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-19648999-C-T is Pathogenic according to our data. Variant chr17-19648999-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188833.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr17-19648999-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH3A2	NM_000382.3	c.28C>T	p.Gln10Ter	stop_gained	1/10	ENST00000176643.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH3A2	ENST00000176643.11	c.28C>T	p.Gln10Ter	stop_gained	1/10	1	NM_000382.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000514 AC: 1 AN: 194412 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 105310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000653

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: 0.00000419 AC: 6 AN: 1433450 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 710456

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: 0.00000546

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000459 Hom.: 2

Bravo AF: 0.00000378

ExAC AF: 0.00000837 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 07, 2018	The ALDH3A2 c.28C>T (p.Gln10Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein and has been reported in a heterozygous state in a Spanish individual with Sjogren-Larsson syndrome (Rizzo et al. 1999). Cultured skin fibroblasts from this individual were shown to be deficient in FALDH, but the individual's full genotype was not clearly reported. In addition, Sanabria and Coco (2011) report the p.Gln10Ter variant in a heterozygous state in two siblings with Sjogren-Larsson syndrome who were also heterozygous for an in-frame deletion variant; the phase of the variants in these individuals was not reported. Control data are unavailable for the p.Gln10Ter variant, which is reported at a frequency of 0.000383 in the East Asian population of the Exome Aggregation Consortium. However, this frequency is based on only one allele in a region of poor sequence coverage. Based on the limited evidence available and the potential impact of stop-gained variants, the p.Gln10Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for Sjogren-Larsson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 17, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 20, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 01, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188833). This premature translational stop signal has been observed in individual(s) with Sjogren-Larsson syndrome (PMID: 10577908, 21968182). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln10*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Benign	0.035
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.27	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.51, 0.50, 0.50, 0.63, 0.52, 0.74
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs72547554; hg19: chr17-19552312;