rs182080501
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_025137.4(SPG11):āc.2318T>Gā(p.Val773Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000172 in 1,547,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V773F) has been classified as Uncertain significance.
Frequency
Consequence
NM_025137.4 missense, splice_region
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.2318T>G | p.Val773Gly | missense_variant, splice_region_variant | 13/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.2318T>G | p.Val773Gly | missense_variant, splice_region_variant | 13/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 30AN: 229816Hom.: 0 AF XY: 0.000112 AC XY: 14AN XY: 125204
GnomAD4 exome AF: 0.000175 AC: 244AN: 1395638Hom.: 0 Cov.: 29 AF XY: 0.000178 AC XY: 124AN XY: 696032
GnomAD4 genome ? AF: 0.000144 AC: 22AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2022 | Reported previously in the heterozygous state as a variant of uncertain significance in an individual with ALS; segregation not performed (Shepheard et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33589474) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 13, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Hereditary spastic paraplegia 11 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2022 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 773 of the SPG11 protein (p.Val773Gly). This variant is present in population databases (rs182080501, gnomAD 0.02%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 33589474). ClinVar contains an entry for this variant (Variation ID: 212292). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 28, 2019 | A heterozygous missense variant, NM_025137.3(SPG11):c.2318T>G, has been identified in exon 12 of 40 of the SPG11 gene. The variant is predicted to result in a major amino acid change from valine to glycine at position 773 of the protein (NP_079413.3(SPG11):p.(Val773Gly)). The valine residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.01% (34 heterozygotes, 0 homozygotes). The variant has been previously described as a variant of certain significant (ClinVar, MSeqDR database). A different variant in the same codon resulting in a change to leucine has also been reported as a vaiant of uncertain significance (ClinVar, MSeqDR database). Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 09, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2023 | The c.2318T>G (p.V773G) alteration is located in exon 13 (coding exon 13) of the SPG11 gene. This alteration results from a T to G substitution at nucleotide position 2318, causing the valine (V) at amino acid position 773 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 01, 2019 | - - |
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