rs759090170
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_025137.4(SPG11):c.6754+2_6754+3dupTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,597,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
SPG11
NM_025137.4 splice_region, intron
NM_025137.4 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.463
Genes affected
SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-44567420-T-TCA is Pathogenic according to our data. Variant chr15-44567420-T-TCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534883.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=3}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SPG11 | NM_025137.4 | c.6754+2_6754+3dupTG | splice_region_variant, intron_variant | Intron 36 of 39 | ENST00000261866.12 | NP_079413.3 |
Ensembl
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GnomAD3 genomes 0.0000532 AC: 8AN: 150388Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251340Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135874
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GnomAD4 exome AF: 0.000106 AC: 153AN: 1447206Hom.: 0 Cov.: 34 AF XY: 0.000104 AC XY: 75AN XY: 719980
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GnomAD4 genome 0.0000532 AC: 8AN: 150468Hom.: 0 Cov.: 31 AF XY: 0.0000681 AC XY: 5AN XY: 73394
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:3
| Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2X (MIM#6166), spastic paraplegia 11 (MIM#604360), and amyotrophic lateral sclerosis 5, juvenile, (MIM#602099). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (8 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable non-canonical splice site variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and as a variant of unknown significance in ClinVar. It has also been reported in the literature in two compound heterozygous individuals with hereditary spastic paraplegia (PMID: 27180005, 18717728). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 26, 2024 | This sequence change falls in intron 36 of the SPG11 gene. It does not directly change the encoded amino acid sequence of the SPG11 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs759090170, gnomAD 0.007%). This variant has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 18717728; internal data). 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: 534883). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 09, 2024 | - - |
Hereditary spastic paraplegia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 19, 2023 | Variant summary: SPG11 c.6754+2_6754+3dupTG alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict the variant abolishes a canonical 5' splicing donor site and creates a new cryptic intronic one. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251340 control chromosomes (gnomAD). c.6754+2_6754+3dupTG has been reported in the literature in compound heterozygous individuals affected with Hereditary Spastic Paraplegia, Type 11 (examples: Paisan-Ruiz_2008, Laurencin_2016) with at least one individual also affected with relapsing-remitting multiple sclerosis (Laurencin_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27180005, 18717728). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2022 | The c.6754+2_6754+3dupTG variant results from a duplication of 2 nucleotides between positions c.6754+2 and c.6754+3 and involves the canonical splice donor site after coding exon 36 of the SPG11 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, the exact impact of this duplication on SPG11 splicing and function is currently unknown. This alteration was detected in conjunction with a likely pathogenic variant in SPG11 in an individual with complex hereditary spastic paraplegia (Paisan-Ruiz C et al. Eur J Neurol, 2008 Oct;15:1065-70). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at