rs1555448989
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_025137.4(SPG11):c.5135T>G(p.Met1712Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M1712I) has been classified as Uncertain significance.
Frequency
Consequence
NM_025137.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.5135T>G | p.Met1712Arg | missense_variant | 30/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.5135T>G | p.Met1712Arg | missense_variant | 30/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457988Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2AN XY: 725488
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 02, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1712 of the SPG11 protein (p.Met1712Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 466536). 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 SPG11 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2023 | The c.5135T>G (p.M1712R) alteration is located in exon 30 (coding exon 30) of the SPG11 gene. This alteration results from a T to G substitution at nucleotide position 5135, causing the methionine (M) at amino acid position 1712 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2019 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Amyotrophic lateral sclerosis type 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Charcot-Marie-Tooth disease axonal type 2X Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at