17-19648973-T-A

Position:

chr17-19648973-T-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000382.3(ALDH3A2):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,586,822 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ALDH3A2
NM_000382.3 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.87

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_000382.3 (ALDH3A2) was described as [Likely_pathogenic] in ClinVar as 552722

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-19648973-T-A is Pathogenic according to our data. Variant chr17-19648973-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH3A2	NM_000382.3 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/10	ENST00000176643.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH3A2	ENST00000176643.11 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/10	1	NM_000382.3	P1	P51648-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

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:

0.00000497

AC:

AN:

201014

Hom.:

AF XY:

0.00000919

AC XY:

AN XY:

108800

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:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1434610

Hom.:

Cov.:

AF XY:

0.00000422

AC XY:

AN XY:

711102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000364

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sjögren-Larsson syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 26, 2017

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ALDH3A2 protein in which other variant(s) (p.Leu27Pro) have been determined to be pathogenic (PMID: 11408337). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 552666). This variant has not been reported in the literature in individuals affected with ALDH3A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ALDH3A2 mRNA. The next in-frame methionine is located at codon 33. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Benign

0.028

.;T;.;.;T;.;T;.;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.45

MutationTaster

Benign

1.0

D;D;D;D;D

PROVEAN

Benign

-1.6

N;.;.;.;N;.;N;N;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0060

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

Polyphen

0.99, 0.99

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

Vest4

0.68, 0.80, 0.81, 0.70, 0.86, 0.83, 0.86

MutPred

0.85

Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);Gain of ubiquitination at M1 (P = 0.0408);

MVP

0.96

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.92

gMVP

0.74

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