6-134929063-A-C

Position:

• chr6-134929063-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022568.4(ALDH8A1):​c.1002T>G​(p.His334Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ALDH8A1 NM_022568.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH8A1	NM_022568.4	c.1002T>G	p.His334Gln	missense_variant	6/7	ENST00000265605.7	NP_072090.1
ALDH8A1	NM_001193480.2	c.852T>G	p.His284Gln	missense_variant	5/6		NP_001180409.1
ALDH8A1	NM_170771.3	c.849+3713T>G		intron_variant			NP_739577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH8A1	ENST00000265605.7	c.1002T>G	p.His334Gln	missense_variant	6/7	1	NM_022568.4	ENSP00000265605	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2023

The c.1002T>G (p.H334Q) alteration is located in exon 6 (coding exon 6) of the ALDH8A1 gene. This alteration results from a T to G substitution at nucleotide position 1002, causing the histidine (H) at amino acid position 334 to be replaced by a glutamine (Q). 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	0.80
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.70	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.73		Gain of MoRF binding (P = 0.0947);.;
MVP		0.77
MPC		0.64
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.86

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.

Other links and lift over

hg19: chr6-135250201;