chr15-44615364-T-C
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_025137.4(SPG11):āc.3037A>Gā(p.Lys1013Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,368 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_025137.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SPG11 | NM_025137.4 | c.3037A>G | p.Lys1013Glu | missense_variant, splice_region_variant | Exon 16 of 40 | ENST00000261866.12 | NP_079413.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00946 AC: 1440AN: 152228Hom.: 8 Cov.: 32
GnomAD3 exomes AF: 0.0102 AC: 2564AN: 251164Hom.: 30 AF XY: 0.0107 AC XY: 1448AN XY: 135736
GnomAD4 exome AF: 0.0116 AC: 16941AN: 1461022Hom.: 129 Cov.: 31 AF XY: 0.0118 AC XY: 8553AN XY: 726848
GnomAD4 genome AF: 0.00946 AC: 1441AN: 152346Hom.: 8 Cov.: 32 AF XY: 0.00961 AC XY: 716AN XY: 74498
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Benign:6
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
The heterozygous p.Lys1013Glu variant in SPG11 has been identified in 2 individuals with spastic paraplegia and no other variant identified in the gene (PMID: 23733235), but has also been identified in >1% of European (non-Finnish) chromosomes and 19 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for spastic paraplegia. -
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not specified Benign:5
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Amyotrophic lateral sclerosis Uncertain:1
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Hereditary spastic paraplegia Benign:1
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not provided Benign:1
SPG11: BP4, BS1, BS2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at