6-134918860-C-A

Variant names:

• chr6-134918860-C-A
• rs756650191
• NM_022568.4:c.1019G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022568.4(ALDH8A1):​c.1019G>T​(p.Ser340Ile) 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. 13/22 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.819

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38916907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH8A1	NM_022568.4	c.1019G>T	p.Ser340Ile	missense_variant	Exon 7 of 7	ENST00000265605.7	NP_072090.1
ALDH8A1	NM_001193480.2	c.869G>T	p.Ser290Ile	missense_variant	Exon 6 of 6		NP_001180409.1
ALDH8A1	NM_170771.3	c.857G>T	p.Ser286Ile	missense_variant	Exon 6 of 6		NP_739577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH8A1	ENST00000265605.7	c.1019G>T	p.Ser340Ile	missense_variant	Exon 7 of 7	1	NM_022568.4	ENSP00000265605.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460666 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726386

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111006

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.0047	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.60	D;.;.;D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Uncertain	2.7	M;.;.;.
PhyloP100		0.82
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.8	D;N;D;D
REVEL	Benign	0.22
Sift	Benign	0.057	T;T;T;D
Sift4G	Uncertain	0.025	D;T;D;.
Polyphen		0.87	P;P;.;.
Vest4		0.28
MutPred		0.59		Loss of disorder (P = 0.0424);.;.;.;
MVP		0.79
MPC		0.36
ClinPred		0.81	D
GERP RS		1.3
Varity_R		0.38
gMVP		0.71
Mutation Taster		=87/13	polymorphism

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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Other links and lift over

dbSNP: rs756650191; hg19: chr6-135239998;