rs72547573

Positions:

chr17-19663486-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000382.3(ALDH3A2):c.1094C>T(p.Ser365Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,836 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ALDH3A2
NM_000382.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.58

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 17-19663486-C-T is Pathogenic according to our data. Variant chr17-19663486-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19663486-C-T is described in Lovd as [Pathogenic]. Variant chr17-19663486-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH3A2	NM_000382.3 linkuse as main transcript	c.1094C>T	p.Ser365Leu	missense_variant	7/10	ENST00000176643.11	NP_000373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH3A2	ENST00000176643.11 linkuse as main transcript	c.1094C>T	p.Ser365Leu	missense_variant	7/10	1	NM_000382.3	ENSP00000176643	P1	P51648-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sjögren-Larsson syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2023	Variant summary: ALDH3A2 c.1094C>T (p.Ser365Leu) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR016161) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251160 control chromosomes. c.1094C>T has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome (examples, Abdel_2019, Rizzo_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 3% of normal activity in FAA-K1A cells (Rizzo_1999). The following publications have been ascertained in the context of this evaluation (PMID: 31273323, 10577908). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 10, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 19965611). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH3A2 protein function. ClinVar contains an entry for this variant (Variation ID: 371221). This missense change has been observed in individual(s) with Sjogren-Larsson syndrome (PMID: 9829906, 17902024, 31273323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 365 of the ALDH3A2 protein (p.Ser365Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Benign

0.90

DEOGEN2

Pathogenic

0.86

.;D;.;D;.;D;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

1.0

.;D;.;.;D;.;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.3

.;H;H;H;H;H;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.2

.;D;.;D;D;.;.;.

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;D;.;D;D;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;D;D;D;.;.

Vest4

0.89

MutPred

0.97

Loss of methylation at K369 (P = 0.1771);Loss of methylation at K369 (P = 0.1771);Loss of methylation at K369 (P = 0.1771);Loss of methylation at K369 (P = 0.1771);Loss of methylation at K369 (P = 0.1771);Loss of methylation at K369 (P = 0.1771);.;.;

MVP

0.97

MPC

0.78

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over