rs887241

Positions:

• chr17-19742625-A-C
• chr17-19742625-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000691.5(ALDH3A1):​c.400T>G​(p.Ser134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,613,612 control chromosomes in the GnomAD database, including 370,348 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.68 (35308 hom., cov: 33)
  • Exomes 𝑓: 0.67 (335040 hom.)
• Consequence: ALDH3A1 NM_000691.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8962734E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH3A1	NM_000691.5	c.400T>G	p.Ser134Ala	missense_variant	4/11	ENST00000225740.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH3A1	ENST00000225740.11	c.400T>G	p.Ser134Ala	missense_variant	4/11	1	NM_000691.5	P1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103084 AN: 151928 Hom.: 35273 Cov.: 33

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.674

GnomAD3 exomes AF: 0.706 AC: 177235 AN: 251140 Hom.: 63456 AF XY: 0.702 AC XY: 95312 AN XY: 135752

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.779

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.947

Gnomad SAS exome AF: 0.736

Gnomad FIN exome AF: 0.661

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.675 AC: 985853 AN: 1461566 Hom.: 335040 Cov.: 69 AF XY: 0.676 AC XY: 491422 AN XY: 727088

Gnomad4 AFR exome AF: 0.648

Gnomad4 AMR exome AF: 0.771

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.951

Gnomad4 SAS exome AF: 0.734

Gnomad4 FIN exome AF: 0.663

Gnomad4 NFE exome AF: 0.660

Gnomad4 OTH exome AF: 0.669

GnomAD4 genome AF: 0.679 AC: 103174 AN: 152046 Hom.: 35308 Cov.: 33 AF XY: 0.683 AC XY: 50732 AN XY: 74316

Gnomad4 AFR AF: 0.652

Gnomad4 AMR AF: 0.736

Gnomad4 ASJ AF: 0.596

Gnomad4 EAS AF: 0.946

Gnomad4 SAS AF: 0.753

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.678

Alfa AF: 0.666 Hom.: 79892

Bravo AF: 0.681

TwinsUK AF: 0.669 AC: 2482

ALSPAC AF: 0.649 AC: 2502

ESP6500AA AF: 0.643 AC: 2833

ESP6500EA AF: 0.659 AC: 5664

ExAC AF: 0.704 AC: 85457

Asia WGS AF: 0.849 AC: 2950 AN: 3478

EpiCase AF: 0.656

EpiControl AF: 0.651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.2
DANN	Benign	0.55
DEOGEN2	Benign	0.083	.;T;T;T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.43	T;T;.;T;.;T;T
MetaRNN	Benign	0.0000029	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.92	.;.;N;N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	2.4	N;.;N;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.69	T;.;T;T;T;T;.
Sift4G	Benign	0.50	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;B;.;.
Vest4		0.061
MPC		0.18
ClinPred		0.00030	T
GERP RS		3.6
Varity_R		0.075
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs887241; hg19: chr17-19645938; COSMIC: COSV56734903; COSMIC: COSV56734903;