rs142712849
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000371224.7(ALDH18A1):āc.1264C>Gā(p.Leu422Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000085 ( 0 hom., cov: 31)
Exomes š: 0.00014 ( 0 hom. )
Consequence
ALDH18A1
ENST00000371224.7 missense
ENST00000371224.7 missense
Scores
15
4
Clinical Significance
Conservation
PhyloP100: 2.58
Genes affected
ALDH18A1 (HGNC:9722): (aldehyde dehydrogenase 18 family member A1) This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH18A1 | NM_002860.4 | c.1264C>G | p.Leu422Val | missense_variant | 12/18 | ENST00000371224.7 | NP_002851.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALDH18A1 | ENST00000371224.7 | c.1264C>G | p.Leu422Val | missense_variant | 12/18 | 1 | NM_002860.4 | ENSP00000360268 | P3 | |
ALDH18A1 | ENST00000371221.3 | c.1258C>G | p.Leu420Val | missense_variant | 12/18 | 1 | ENSP00000360265 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152096Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
13
AN:
152096
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000760 AC: 19AN: 249956Hom.: 0 AF XY: 0.0000740 AC XY: 10AN XY: 135206
GnomAD3 exomes
AF:
AC:
19
AN:
249956
Hom.:
AF XY:
AC XY:
10
AN XY:
135206
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000137 AC: 200AN: 1461054Hom.: 0 Cov.: 33 AF XY: 0.000125 AC XY: 91AN XY: 726806
GnomAD4 exome
AF:
AC:
200
AN:
1461054
Hom.:
Cov.:
33
AF XY:
AC XY:
91
AN XY:
726806
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152212Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8AN XY: 74436
GnomAD4 genome
AF:
AC:
13
AN:
152212
Hom.:
Cov.:
31
AF XY:
AC XY:
8
AN XY:
74436
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
8
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
de Barsy syndrome;C4225268:Cutis laxa, autosomal dominant 3;C5568978:Hereditary spastic paraplegia 9A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 28, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 422 of the ALDH18A1 protein (p.Leu422Val). This variant is present in population databases (rs142712849, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALDH18A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 464038). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at