Variant 6-134918860-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022568.4(ALDH8A1):c.1019G>C(p.Ser340Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ALDH8A1
NM_022568.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.819

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;

BP4

Computational evidence support a benign effect (MetaRNN=0.28645378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH8A1	NM_022568.4 linkuse as main transcript	c.1019G>C	p.Ser340Thr	missense_variant	7/7	ENST00000265605.7	NP_072090.1
ALDH8A1	NM_001193480.2 linkuse as main transcript	c.869G>C	p.Ser290Thr	missense_variant	6/6		NP_001180409.1
ALDH8A1	NM_170771.3 linkuse as main transcript	c.857G>C	p.Ser286Thr	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.1019G>C	p.Ser340Thr	missense_variant	7/7	1	NM_022568.4	ENSP00000265605	P1	Q9H2A2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460666

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

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

Jun 06, 2023

The c.1019G>C (p.S340T) alteration is located in exon 7 (coding exon 7) of the ALDH8A1 gene. This alteration results from a G to C substitution at nucleotide position 1019, causing the serine (S) at amino acid position 340 to be replaced by a threonine (T). 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

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.23

T;.;.;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

D;T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.7

L;.;.;.

MutationTaster

Benign

0.95

D;D;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.11

T;T;T;.

Polyphen

0.66

P;P;.;.

Vest4

0.063

MutPred

0.60

Loss of MoRF binding (P = 0.1169);.;.;.;

MVP

0.55

MPC

0.15

ClinPred

0.25

GERP RS

1.3

Varity_R

0.10

gMVP

0.57

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over