Variant 6-134939315-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000265605.7(ALDH8A1):c.543G>C(p.Glu181Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ALDH8A1
ENST00000265605.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH8A1	NM_022568.4 linkuse as main transcript	c.543G>C	p.Glu181Asp	missense_variant	4/7	ENST00000265605.7	NP_072090.1
ALDH8A1	NM_170771.3 linkuse as main transcript	c.543G>C	p.Glu181Asp	missense_variant	4/6		NP_739577.1
ALDH8A1	NM_001193480.2 linkuse as main transcript	c.442+3094G>C		intron_variant			NP_001180409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH8A1	ENST00000265605.7 linkuse as main transcript	c.543G>C	p.Glu181Asp	missense_variant	4/7	1	NM_022568.4	ENSP00000265605	P1	Q9H2A2-1
ALDH8A1	ENST00000367845.6 linkuse as main transcript	c.543G>C	p.Glu181Asp	missense_variant	4/6	1		ENSP00000356819		Q9H2A2-2
ALDH8A1	ENST00000349305.8 linkuse as main transcript	c.*101G>C		3_prime_UTR_variant, NMD_transcript_variant	5/7	1		ENSP00000325473		Q9H2A2-3
ALDH8A1	ENST00000367847.2 linkuse as main transcript	c.442+3094G>C		intron_variant		2		ENSP00000356821		Q9H2A2-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251402

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Dec 17, 2023

The c.543G>C (p.E181D) alteration is located in exon 4 (coding exon 4) of the ALDH8A1 gene. This alteration results from a G to C substitution at nucleotide position 543, causing the glutamic acid (E) at amino acid position 181 to be replaced by an aspartic acid (D). 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

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;D

Vest4

0.86

MutPred

0.87

Loss of ubiquitination at K178 (P = 0.093);Loss of ubiquitination at K178 (P = 0.093);

MVP

0.43

MPC

0.61

ClinPred

0.99

GERP RS

5.5

Varity_R

0.90

gMVP

0.91

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