rs72547566

chr17-19657746-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000382.3(ALDH3A2):c.682C>T(p.Arg228Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,604,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ALDH3A2
NM_000382.3 missense, splice_region

Scores

Splicing: ADA: 0.9206

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.87

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 18 ACMG points.

PM1

In a helix (size 12) in uniprot entity AL3A2_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000382.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-19657747-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 653859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 17-19657746-C-T is Pathogenic according to our data. Variant chr17-19657746-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in UniProt as null. Variant chr17-19657746-C-T is described in Lovd as [Pathogenic]. Variant chr17-19657746-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH3A2	NM_000382.3 linkuse as main transcript	c.682C>T	p.Arg228Cys	missense_variant, splice_region_variant	5/10	ENST00000176643.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH3A2	ENST00000176643.11 linkuse as main transcript	c.682C>T	p.Arg228Cys	missense_variant, splice_region_variant	5/10	1	NM_000382.3	P1	P51648-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251432

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000248

AC:

AN:

1451916

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

722988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000317

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74444

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sjögren-Larsson syndrome

Pathogenic:5

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 02, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2022	Published functional studies demonstrate a damaging effect with significant loss of enzyme activity for the R228C mutant at 9% of the wild-type activity (Rizzo et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16476818, 10577908, 30925032, 31456290, 16837225, 28257279, 28471629, 25047030, 27717089, 32395410) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 228 of the ALDH3A2 protein (p.Arg228Cys). This variant is present in population databases (rs72547566, gnomAD 0.003%). This missense change has been observed in individuals with Sj√∂gren‚ÄìLarsson syndrome (PMID: 10577908, 27717089, 28257279, 28471629, 30925032). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 556574). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 10577908). This variant disrupts the p.Arg228 amino acid residue in ALDH3A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22397046, 29704247). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.39

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.95

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

MetaSVM

Uncertain

0.65

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.55

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.94

MVP

0.99

MPC

1.0

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Benign

0.66

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