rs312262778
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_025137.4(SPG11):c.6206-1G>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
SPG11
NM_025137.4 splice_acceptor
NM_025137.4 splice_acceptor
Scores
4
1
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.81
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 Pathogenic. Variant got 10 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.018685216 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-44572821-C-G is Pathogenic according to our data. Variant chr15-44572821-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 41342.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.6206-1G>C | splice_acceptor_variant | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.6206-1G>C | splice_acceptor_variant | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The splice site acceptor c.6206-1G>C variant in SPG11 gene has been reported in compound heterozygous state in individuals affected with Spastic paraplegia (Orlén, Hanna et al.,2009). This variant affects the invariant splice site. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is submitted in ClinVar as Pathogenic. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at