10-95606919-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_002860.4(ALDH18A1):c.2231C>G(p.Ser744Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S744L) has been classified as Uncertain significance.
Frequency
Consequence
NM_002860.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH18A1 | NM_002860.4 | c.2231C>G | p.Ser744Trp | missense_variant | 18/18 | ENST00000371224.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH18A1 | ENST00000371224.7 | c.2231C>G | p.Ser744Trp | missense_variant | 18/18 | 1 | NM_002860.4 | P3 | |
ALDH18A1 | ENST00000371221.3 | c.2225C>G | p.Ser742Trp | missense_variant | 18/18 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251172Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135744
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461834Hom.: 0 Cov.: 34 AF XY: 0.0000413 AC XY: 30AN XY: 727230
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74290
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 5A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 23, 2023 | This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 744 of the ALDH18A1 protein (p.Ser744Trp). This variant is present in population databases (rs762271422, gnomAD 0.04%). 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: 522897). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH18A1 protein function. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at