rs875989878
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_014946.4(SPAST):c.1245+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_014946.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1434890Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 715440
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 4 Pathogenic:10
Variant summary: SPAST c.1245+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in the skipping of exon 9 (Svenson_2001). The variant was absent in 251070 control chromosomes (gnomAD). c.1245+1G>A has been reported in the literature in multiple individuals affected with Spastic Paraplegia 4, including four individuals from an Italian family where it was inherited in an autosomal dominant manner (eg. Svenson_2001, Nanetti_2012, Fei_2011, Zhao_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21834905, 22960362, 11309678, 31630374). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=11)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
PVS1,PS3,PM2 -
This inherited mutation in the SPAST gene is the likely cause of the familial spastic paraplegia observed in the patient and in her father. -
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000226113). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
- -
- -
- -
Variant confirmed as disease-causing by referring clinical team -
This sequence change affects a donor splice site in intron 9 of the SPAST gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hereditary spastic paraplegia (HSP) (PMID: 11309678, 22552817, 22960362, 26600529). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this SPAST variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 3,690 individuals referred to our laboratory for SPAST testing. This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 226113). Studies have shown that disruption of this splice site results in skipping of 9, but is expected to preserve the integrity of the reading-frame (PMID: 11309678, 26600529). For these reasons, this variant has been classified as Pathogenic. -
This sequence change in SPAST occurs within the canonical splice donor site of intron 9. It is predicted to cause skipping of biologically relevant exon 9/17, resulting in an in-frame deletion (removes amino acids 392-415) that is expected to escape nonsense-mediated decay and remove part of the AAA ATPase domain which is critical for protein function (PMID: 26094131). This prediction is confirmed by RNA assays in patient cells and minigene assays (PMID: 11309678, 26600529). This variant is present in a single African/African American individual in the population database gnomAD v4.0 (1/56,710 alleles). This variant has been reported in multiple individuals with pure hereditary spastic paraplegia (HSP) and segregates with HSP in multiple families (PMID: 11309678, 21834905, 22552817, 26600529; ClinVar: SCV000268514.1, SCV001190276.1, SCV001450963.1, SCV002105589.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PP1_Strong, PS4_Moderate, PM2_Supporting. -
not provided Pathogenic:5
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31227335, 25525159, 11309678, 31630374, 29980238, 19875132, 26600529, 22552817, 22960362, 34983064, 37251230, 31594988, 38145127, 21139634, 26094131) -
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is not expected to cause loss of protein expression through nonsense-mediated decay, however, similar variants in this region have been associated with disease, and therefore, this variant is also expected to associate with disease. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. The variant is located in a region that is considered important for protein function and/or structure. -
- -
- -
PVS1, PS3, PS4_moderate, PM1, PM2, PP4 -
SPAST-related spastic paraplegia Pathogenic:1
The SPAST c.1245+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt the normal gene product. Across a selection of the available literature, the c.1245+1G>A variant has been reported in at least four unrelated individuals affected with hereditary spastic paraplegia (Svenson et al. 2001; Magariello et al. 2010; Nanetti et al. 2012; Zhao et al. 2015). The variant was found to segregate among other affected family members (Svenson et al. 2001; Nanetti et al. 2012; Zhao et al. 2015). The age of onset varied from 4-50 years and clinical features included lower limb stiffness, spastic gait and walking difficulty, among others. The variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Experimental studies have shown this variant to result in skipping of exon 9, which encodes for part of the critical ATPase AAA domain of the protein (Svenson et al. 2001). Based on the collective evidence and application of the ACMG criteria, the c.1245+1G>A variant is classified as pathogenic for hereditary spastic paraplegia. -
Inborn genetic diseases Pathogenic:1
- -
Hereditary spastic paraplegia Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at