Genetic Variant NM_022568.4:c.1019G>A (chr6-134918860-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022568.4(ALDH8A1):c.1019G>A(p.Ser340Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S340T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ALDH8A1
NM_022568.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.819

Publications

0 publications found

Variant links:

Genes affected

ALDH8A1 (HGNC:15471): (aldehyde dehydrogenase 8 family member A1) This gene encodes a member of the aldehyde dehydrogenase family of proteins. The encoded protein has been implicated in the synthesis of 9-cis-retinoic acid and in the breakdown of the amino acid tryptophan. This enzyme converts 9-cis-retinal into the retinoid X receptor ligand 9-cis-retinoic acid, and has approximately 40-fold higher activity with 9-cis-retinal than with all-trans-retinal. In addition, this enzyme has been shown to catalyze the conversion of 2-aminomuconic semialdehyde to 2-aminomuconate in the kynurenine pathway of tryptophan catabolism. [provided by RefSeq, Jul 2018]

ALDH8A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15184855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH8A1	NM_022568.4 link	c.1019G>A	p.Ser340Asn	missense_variant	Exon 7 of 7	ENST00000265605.7	NP_072090.1	Q9H2A2-1
ALDH8A1	NM_001193480.2 link	c.869G>A	p.Ser290Asn	missense_variant	Exon 6 of 6		NP_001180409.1	Q9H2A2-4
ALDH8A1	NM_170771.3 link	c.857G>A	p.Ser286Asn	missense_variant	Exon 6 of 6		NP_739577.1	Q9H2A2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH8A1	ENST00000265605.7 link	c.1019G>A	p.Ser340Asn	missense_variant	Exon 7 of 7	1	NM_022568.4	ENSP00000265605.2		Q9H2A2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250214

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460666

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.0000224

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111006

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.15

T;.;.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.77

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

L;.;.;.

PhyloP100

0.82

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.42

T;T;T;.

Polyphen

0.0060

B;B;.;.

Vest4

0.042

MutPred

0.55

Loss of MoRF binding (P = 0.1422);.;.;.;

MVP

0.39

MPC

0.14

ClinPred

0.045

GERP RS

1.3

Varity_R

0.11

gMVP

0.59

Mutation Taster

=84/16

polymorphism

(source)

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

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NM_022568.4:c.1019G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over