chr10-95613990-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002860.4(ALDH18A1):​c.1777A>G​(p.Ser593Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S593T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ALDH18A1
NM_002860.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.61

Publications

0 publications found
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]
ALDH18A1 Gene-Disease associations (from GenCC):
  • cutis laxa, autosomal dominant 3
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • ALDH18A1-related de Barsy syndrome
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • autosomal recessive complex spastic paraplegia type 9B
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
  • P5CS deficiency
    Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
  • hereditary spastic paraplegia 9A
    Inheritance: AD, SD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
  • autosomal dominant complex spastic paraplegia type 9B
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal dominant cutis laxa
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALDH18A1NM_002860.4 linkc.1777A>G p.Ser593Gly missense_variant Exon 14 of 18 ENST00000371224.7 NP_002851.2 P54886-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALDH18A1ENST00000371224.7 linkc.1777A>G p.Ser593Gly missense_variant Exon 14 of 18 1 NM_002860.4 ENSP00000360268.2 P54886-1
ALDH18A1ENST00000371221.3 linkc.1771A>G p.Ser591Gly missense_variant Exon 14 of 18 1 ENSP00000360265.3 P54886-2
ALDH18A1ENST00000485428.1 linkn.393A>G non_coding_transcript_exon_variant Exon 2 of 4 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251172
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 Uncertain:1
Nov 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 593 of the ALDH18A1 protein (p.Ser593Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 464040). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ALDH18A1 protein function with a negative predictive value of 95%. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;.
Eigen
Benign
0.058
Eigen_PC
Benign
0.16
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.035
D
MetaRNN
Uncertain
0.47
T;T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
1.9
L;.
PhyloP100
4.6
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-1.4
N;N
REVEL
Uncertain
0.38
Sift
Uncertain
0.014
D;D
Sift4G
Uncertain
0.015
D;D
Polyphen
0.21
B;B
Vest4
0.57
MutPred
0.56
Loss of stability (P = 0.0368);.;
MVP
0.67
MPC
0.29
ClinPred
0.55
D
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.37
gMVP
0.62
Mutation Taster
=80/20
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1231068982; hg19: chr10-97373747; API