17-19739598-G-C

Variant names:

• chr17-19739598-G-C
• rs761187992
• NM_000691.5:c.1026C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000691.5(ALDH3A1):​c.1026C>G​(p.Ile342Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I342I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH3A1 NM_000691.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.803
• Publications: 1 publications found

Genes affected

ALDH3A1 (HGNC:405): (aldehyde dehydrogenase 3 family member A1) Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-derived acetaldehyde and in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. The enzyme encoded by this gene forms a cytoplasmic homodimer that preferentially oxidizes aromatic and medium-chain (6 carbons or more) saturated and unsaturated aldehyde substrates. It is thought to promote resistance to UV and 4-hydroxy-2-nonenal-induced oxidative damage in the cornea. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000691.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A1	NM_000691.5	MANE Select	c.1026C>G	p.Ile342Met	missense	Exon 8 of 11	NP_000682.3
	ALDH3A1	NM_001135167.1		c.1026C>G	p.Ile342Met	missense	Exon 8 of 11	NP_001128639.1	P30838
	ALDH3A1	NM_001135168.1		c.1026C>G	p.Ile342Met	missense	Exon 7 of 10	NP_001128640.1	P30838

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A1	ENST00000225740.11	TSL:1 MANE Select	c.1026C>G	p.Ile342Met	missense	Exon 8 of 11	ENSP00000225740.6	P30838
	ALDH3A1	ENST00000457500.6	TSL:1	c.1026C>G	p.Ile342Met	missense	Exon 7 of 10	ENSP00000411821.2	P30838
	ALDH3A1	ENST00000905965.1		c.1047C>G	p.Ile349Met	missense	Exon 8 of 11	ENSP00000576024.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.025
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.26	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-0.80
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.76		Loss of catalytic residue at V343 (P = 0.1433)
MVP		0.72
MPC		0.83
ClinPred		0.98	D
GERP RS		0.96
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

Other links and lift over

dbSNP: rs761187992; hg19: chr17-19642911;