rs144012151
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_025137.4(SPG11):āc.2075T>Cā(p.Ile692Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000195 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_025137.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.2075T>C | p.Ile692Thr | missense_variant | Exon 11 of 40 | ENST00000261866.12 | NP_079413.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000116 AC: 29AN: 250536Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135422
GnomAD4 exome AF: 0.000203 AC: 297AN: 1461368Hom.: 0 Cov.: 31 AF XY: 0.000194 AC XY: 141AN XY: 726958
GnomAD4 genome AF: 0.000118 AC: 18AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:3
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26556829) -
SPG11: PM2 -
- -
Hereditary spastic paraplegia 11 Uncertain:3
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 692 of the SPG11 protein (p.Ile692Thr). This variant is present in population databases (rs144012151, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 425067). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
- -
The c.2075T>C (p.Ile692Thr) missense variant in SPG11 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.01%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as a Variant of Uncertain Significance. The amino acid Ile at position 692 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile692Thr in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -
Inborn genetic diseases Uncertain:1
The p.I692T variant (also known as c.2075T>C), located in coding exon 11 of the SPG11 gene, results from a T to C substitution at nucleotide position 2075. The isoleucine at codon 692 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Amyotrophic lateral sclerosis type 5 Uncertain:1
- -
Charcot-Marie-Tooth disease axonal type 2X Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at