dbSNP rs72547566: ALDH3A2:p.Arg228Gly (chr17-19657746-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000382.3(ALDH3A2):c.682C>G(p.Arg228Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALDH3A2
NM_000382.3 missense, splice_region

Scores

Splicing: ADA: 0.6968

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a helix (size 12) in uniprot entity AL3A2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr17-19657746-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH3A2	NM_000382.3 link	c.682C>G	p.Arg228Gly	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000176643.11	NP_000373.1	P51648-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH3A2	ENST00000176643.11 link	c.682C>G	p.Arg228Gly	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_000382.3	ENSP00000176643.6		P51648-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451914

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722986

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:

9.07e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

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

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.92

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

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.4

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

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-6.8

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.94

MutPred

0.73

Loss of stability (P = 0.0261);Loss of stability (P = 0.0261);Loss of stability (P = 0.0261);Loss of stability (P = 0.0261);Loss of stability (P = 0.0261);Loss of stability (P = 0.0261);.;

MVP

0.97

MPC

0.98

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.70

dbscSNV1_RF

Benign

0.50

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over