rs368147360

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002860.4(ALDH18A1):​c.868G>A​(p.Gly290Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

ALDH18A1
NM_002860.4 missense

Scores

6
4
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.46
Variant links:
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 UniProt
ALDH18A1NM_002860.4 linkuse as main transcriptc.868G>A p.Gly290Arg missense_variant 8/18 ENST00000371224.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALDH18A1ENST00000371224.7 linkuse as main transcriptc.868G>A p.Gly290Arg missense_variant 8/181 NM_002860.4 P3P54886-1
ALDH18A1ENST00000371221.3 linkuse as main transcriptc.862G>A p.Gly288Arg missense_variant 8/181 A1P54886-2
ALDH18A1ENST00000489386.1 linkuse as main transcriptn.233G>A non_coding_transcript_exon_variant 2/53

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000637
AC:
16
AN:
251312
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000435
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000486
AC:
71
AN:
1461790
Hom.:
0
Cov.:
31
AF XY:
0.0000495
AC XY:
36
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000277
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000441
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cutis laxa, autosomal dominant 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsFeb 01, 2019This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 29, 2023In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ALDH18A1 protein function. ClinVar contains an entry for this variant (Variation ID: 464043). This variant has not been reported in the literature in individuals affected with ALDH18A1-related conditions. This variant is present in population databases (rs368147360, gnomAD 0.05%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 290 of the ALDH18A1 protein (p.Gly290Arg). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 18, 2024Has 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 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.31
T;.
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.97
D;D
M_CAP
Benign
0.050
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
1.6
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-1.7
N;N
REVEL
Uncertain
0.33
Sift
Benign
0.35
T;T
Sift4G
Benign
0.20
T;T
Polyphen
1.0
D;D
Vest4
0.78
MutPred
0.42
Gain of solvent accessibility (P = 0.0306);.;
MVP
0.54
MPC
2.0
ClinPred
0.26
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.28
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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.

Other links and lift over

dbSNP: rs368147360; hg19: chr10-97388190; COSMIC: COSV64662043; API