rs312262755
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.3664_3665insT(p.Lys1222IlefsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000192 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_025137.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.3664_3665insT | p.Lys1222IlefsTer15 | frameshift_variant | Exon 21 of 40 | ENST00000261866.12 | NP_079413.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251402Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135884
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727218
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:2Other:1
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This sequence change creates a premature translational stop signal (p.Lys1222Ilefs*15) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs312262755, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 19105190, 23043354, 23733235). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41309). For these reasons, this variant has been classified as Pathogenic. -
Spastic paraplegia Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.3664_3665insT pathogenic mutation, located in coding exon 21 of the SPG11 gene, results from an insertion of one nucleotide at position 3664, causing a translational frameshift with a predicted alternate stop codon (p.K1222Ifs*15). This alteration was reported in the homozygous form in several affected members of a family who presented at age 12 to 21 years with walking instability (Hammer MB et al. Eur. J. Neurol., 2013 Mar;20:486-92). Pyramidal syndrome with spasticity and Babinski sign was present in all patients, while gait ataxia and dysarthria were initial signs in two of them. This alteration has also been reported heterozygous in trans with other pathogenic SPG11 mutations in multiple affected individuals with hereditary spastic paraplegia (Denora PS et al. Hum. Mutat., 2009 Mar;30:E500-19; Guidubaldi A et al. Mov. Disord., 2011 Feb;26:553-6). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at