Variant 6-134918816-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP3BP4_Moderate

The NM_022568.4(ALDH8A1):c.1063G>A(p.Gly355Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

ALDH8A1
NM_022568.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.60

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.25436556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH8A1	NM_022568.4 linkuse as main transcript	c.1063G>A	p.Gly355Ser	missense_variant	7/7	ENST00000265605.7	NP_072090.1
ALDH8A1	NM_001193480.2 linkuse as main transcript	c.913G>A	p.Gly305Ser	missense_variant	6/6		NP_001180409.1
ALDH8A1	NM_170771.3 linkuse as main transcript	c.901G>A	p.Gly301Ser	missense_variant	6/6		NP_739577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH8A1	ENST00000265605.7 linkuse as main transcript	c.1063G>A	p.Gly355Ser	missense_variant	7/7	1	NM_022568.4	ENSP00000265605	P1	Q9H2A2-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000406

AC:

102

AN:

251278

Hom.:

AF XY:

0.000538

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000306

AC:

448

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

276

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000218

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000217

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.1063G>A (p.G355S) alteration is located in exon 7 (coding exon 7) of the ALDH8A1 gene. This alteration results from a G to A substitution at nucleotide position 1063, causing the glycine (G) at amino acid position 355 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.;.;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

2.9

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.90

MVP

0.93

MPC

0.64

ClinPred

0.37

GERP RS

5.7

Varity_R

0.78

gMVP

0.96

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