rs312262748
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The ENST00000261866.12(SPG11):āc.2833A>Gā(p.Arg945Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,459,048 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 Pathogenic (ā ).
Frequency
Consequence
ENST00000261866.12 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.2833A>G | p.Arg945Gly | missense_variant, splice_region_variant | 15/40 | ENST00000261866.12 | NP_079413.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.2833A>G | p.Arg945Gly | missense_variant, splice_region_variant | 15/40 | 1 | NM_025137.4 | ENSP00000261866 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459048Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726082
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 21, 2023 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 945 of the SPG11 protein (p.Arg945Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) (PMID: 18079167, 19105190, 19196735, 26556829, 27077743). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41298). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at