17-19648999-C-G

Position:

chr17-19648999-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000382.3(ALDH3A2):c.28C>G(p.Gln10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,585,796 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 24 hom. )

Consequence

ALDH3A2
NM_000382.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.770

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008210927).

BP6

Variant 17-19648999-C-G is Benign according to our data. Variant chr17-19648999-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495853.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr17-19648999-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00403 (614/152352) while in subpopulation NFE AF= 0.00711 (484/68034). AF 95% confidence interval is 0.00659. There are 1 homozygotes in gnomad4. There are 279 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH3A2	NM_000382.3 linkuse as main transcript	c.28C>G	p.Gln10Glu	missense_variant	1/10	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.28C>G	p.Gln10Glu	missense_variant	1/10	1	NM_000382.3	ENSP00000176643	P1	P51648-1

Frequencies

GnomAD3 genomes

AF:

0.00402

AC:

612

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00137

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00711

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00361

AC:

702

AN:

194412

Hom.:

AF XY:

0.00379

AC XY:

399

AN XY:

105310

show subpopulations

Gnomad AFR exome

AF:

0.000971

Gnomad AMR exome

AF:

0.000802

Gnomad ASJ exome

AF:

0.00172

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000578

Gnomad FIN exome

AF:

0.00355

Gnomad NFE exome

AF:

0.00677

Gnomad OTH exome

AF:

0.00401

GnomAD4 exome

AF:

0.00563

AC:

8066

AN:

1433444

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

3928

AN XY:

710452

show subpopulations

Gnomad4 AFR exome

AF:

0.000903

Gnomad4 AMR exome

AF:

0.000899

Gnomad4 ASJ exome

AF:

0.00158

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000571

Gnomad4 FIN exome

AF:

0.00417

Gnomad4 NFE exome

AF:

0.00680

Gnomad4 OTH exome

AF:

0.00391

GnomAD4 genome

AF:

0.00403

AC:

614

AN:

152352

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

279

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.00711

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00341

Hom.:

Bravo

AF:

0.00357

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000692

AC:

ESP6500EA

AF:

0.00648

AC:

ExAC

AF:

0.00344

AC:

411

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 25, 2016	Variant summary: The ALDH3A2 c.28C>G (p.Gln10Glu) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 265/30662 (1/115, 1 homozygote), predominantly in the European (Non-Finnish) cohort, 249/14168 (1/56). Therefore, suggesting the variant of interest is a common polymorphism found in populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2021	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ALDH3A2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Sjögren-Larsson syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ALDH3A2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.081

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

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.38

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

MetaRNN

Benign

0.0082

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.29

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

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.72

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

REVEL

Benign

0.085

Sift

Benign

1.0

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

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;.;.;B;B;B;B;B

Vest4

0.073, 0.043, 0.046, 0.090, 0.080, 0.056, 0.097

MVP

0.60

MPC

0.25

ClinPred

0.0029

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.15

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