17-19648999-C-T

Variant names:

• chr17-19648999-C-T
• rs72547554
• NM_000382.3:c.28C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000382.3(ALDH3A2):​c.28C>T​(p.Gln10*) 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ALDH3A2 NM_000382.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.770
• Publications: 8 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 syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 138 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 Pathogenic. ClinVar VariationId is 188833.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000382.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A2	NM_000382.3	MANE Select	c.28C>T	p.Gln10*	stop_gained	Exon 1 of 10	NP_000373.1	P51648-1
	ALDH3A2	NM_001031806.2		c.28C>T	p.Gln10*	stop_gained	Exon 1 of 11	NP_001026976.1	P51648-2
	ALDH3A2	NM_001369136.1		c.28C>T	p.Gln10*	stop_gained	Exon 2 of 12	NP_001356065.1	P51648-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A2	ENST00000176643.11	TSL:1 MANE Select	c.28C>T	p.Gln10*	stop_gained	Exon 1 of 10	ENSP00000176643.6	P51648-1
	ALDH3A2	ENST00000339618.8	TSL:1	c.28C>T	p.Gln10*	stop_gained	Exon 1 of 11	ENSP00000345774.4	P51648-2
	ALDH3A2	ENST00000671878.1		c.28C>T	p.Gln10*	stop_gained	Exon 1 of 10	ENSP00000500516.1	A0A5F9ZHN9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000514 AC: 1 AN: 194412 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33220

American (AMR) AF: 0.00 AC: 0 AN: 40066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25382

East Asian (EAS) AF: 0.00 AC: 0 AN: 38682

South Asian (SAS) AF: 0.00 AC: 0 AN: 82336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00000546 AC: 6 AN: 1098828

Other (OTH) AF: 0.00 AC: 0 AN: 59266

GnomAD4 genome Cov.: 33

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.00000378

ExAC AF: 0.00000837 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Sjögren-Larsson syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.77
Vest4		0.51
GERP RS		2.2
PromoterAI		0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs72547554; hg19: chr17-19552312;