rs150571352
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_025137.4(SPG11):c.7132T>C(p.Phe2378Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
SPG11
NM_025137.4 missense
NM_025137.4 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 4.81
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000133 (195/1461702) while in subpopulation MID AF= 0.00663 (38/5728). AF 95% confidence interval is 0.00497. There are 0 homozygotes in gnomad4_exome. There are 108 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.7132T>C | p.Phe2378Leu | missense_variant | 39/40 | ENST00000261866.12 | NP_079413.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.7132T>C | p.Phe2378Leu | missense_variant | 39/40 | 1 | NM_025137.4 | ENSP00000261866.7 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000203 AC: 51AN: 251000Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135790
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GnomAD4 exome AF: 0.000133 AC: 195AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108AN XY: 727160
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74368
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 06, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2378 of the SPG11 protein (p.Phe2378Leu). This variant is present in population databases (rs150571352, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SPG11-related conditions (PMID: 27066562). ClinVar contains an entry for this variant (Variation ID: 216774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 11, 2022 | This SPG11 variant (rs150571352) is rare (<0.1%) in a large population dataset (gnomAD: 52/282406 total alleles; 0.02%; no homozygotes) and has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be damaging while another predicts that it would be tolerated. The phenylalanine residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 39 splicing, although this has not been confirmed experimentally to our knowledge. This variant was identified in a homozygous state in a single family with juvenile motor neuron disease. However, an additional homozygous nonsense variant in the SPG11 gene (c.2250delT) was also identified in affected family members making the functional impact of c.7132T>C alone unclear. Due to insufficient evidence, we consider the clinical significance of c.7132T>C to be uncertain at this time. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 27, 2023 | The c.7132T>C (p.F2378L) alteration is located in exon 39 (coding exon 39) of the SPG11 gene. This alteration results from a T to C substitution at nucleotide position 7132, causing the phenylalanine (F) at amino acid position 2378 to be replaced by a leucine (L). The altered amino acid is well conserved throughout evolution:_x000D_ _x000D_ The p.F2378 amino acid is conserved in available primate species. The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.F2378L alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 02, 2024 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 14, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 27, 2023 | - - |
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Amyotrophic lateral sclerosis type 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 05, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2018 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;T
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of disorder (P = 0.0827);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at