rs72547568

Positions:

chr17-19657797-G-A

Variant summary

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

The NM_000382.3(ALDH3A2):c.733G>A(p.Asp245Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,922 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: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ALDH3A2
NM_000382.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 9.87

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, 0.98

PP5

Variant 17-19657797-G-A is Pathogenic according to our data. Variant chr17-19657797-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19657797-G-A is described in Lovd as [Pathogenic]. Variant chr17-19657797-G-A 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.733G>A	p.Asp245Asn	missense_variant	5/10	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.733G>A	p.Asp245Asn	missense_variant	5/10	1	NM_000382.3	ENSP00000176643	P1	P51648-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251450

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sjögren-Larsson syndrome

Pathogenic:3Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 01-10-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 09, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 31, 2020	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozygous p.Asp245Asn variant was identified by our study in two individuals with Sjogren-Larsson Syndrome. The p.Asp245Asn variant is believed to be pathogenic based on numberous reports in the literature and databases. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 05, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 245 of the ALDH3A2 protein (p.Asp245Asn). This variant is present in population databases (rs72547568, gnomAD 0.002%). This missense change has been observed in individual(s) with Sjoegren-Larsson syndrome (PMID: 10577908, 11408337, 21872273). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been described in the literature as part of a complex haplotype in individuals affected with Sjoegren-Larsson syndrome with European heritage (PMID: 29183715, 9829906). In these individuals this variant is described in combination with a complex variant involving three separate sequence changes that occur on the same chromosome (in cis) (c.901 G>C; c.906delT; and c.909 T>G). ClinVar contains an entry for this complex haplotype (Variation ID: 438264). ClinVar contains an entry for this variant (Variation ID: 265459). 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. Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 10577908). In summary, this is a rare variant that has been observed as part of a complex European haplotype with a second pathogenic variant. It has been observed in several individuals with Sj√∂gren-Larsson syndrome, and is expected to affect ALDH3A2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	ALDH3A2: PM2, PM3, PS4:Moderate, PS3:Supporting, BP2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	Published functional studies demonstrate that the D245N variant almost completely abolishes the enzymatic activity of the protein (Rizzo et al., 1999); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21872273, 11408337, 10577908, 11306053, 9829906, 16996289, 15931689, 29183715) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Benign

0.92

DEOGEN2

Uncertain

0.74

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.7

.;M;M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.9

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

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.93

MutPred

0.95

Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);.;

MVP

0.99

MPC

0.84

ClinPred

0.99

GERP RS

5.1

Varity_R

0.90

gMVP

0.88

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