dbSNP rs72547572: ALDH3A2:p.Met328Ile (chr17-19663376-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000382.3(ALDH3A2):c.984G>A(p.Met328Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,224 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ALDH3A2
NM_000382.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.90

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 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH3A2	NM_000382.3 link	c.984G>A	p.Met328Ile	missense_variant	Exon 7 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.984G>A	p.Met328Ile	missense_variant	Exon 7 of 10	1	NM_000382.3	ENSP00000176643.6		P51648-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Sjögren-Larsson syndrome

Uncertain:1

May 22, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.3

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

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.94

Sift

Uncertain

0.017

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

Sift4G

Uncertain

0.012

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

Polyphen

1.0

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

Vest4

0.88

MutPred

0.90

Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);.;.;

MVP

0.99

MPC

0.86

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.87

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