rs1555448900

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025137.4(SPG11):​c.5426A>G​(p.His1809Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SPG11
NM_025137.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.15
Variant links:
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12720188).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPG11NM_025137.4 linkuse as main transcriptc.5426A>G p.His1809Arg missense_variant 30/40 ENST00000261866.12 NP_079413.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPG11ENST00000261866.12 linkuse as main transcriptc.5426A>G p.His1809Arg missense_variant 30/401 NM_025137.4 ENSP00000261866 Q96JI7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 24, 2017In summary, this variant has uncertain impact on SPG11 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with an SPG11-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 1809 of the SPG11 protein (p.His1809Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.014
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
15
DANN
Benign
0.96
DEOGEN2
Benign
0.029
T;.;T;.
Eigen
Benign
-0.16
Eigen_PC
Benign
0.016
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.77
T;T;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.2
M;M;.;M
MutationTaster
Benign
0.78
N;N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.7
N;N;N;N
REVEL
Benign
0.16
Sift
Benign
0.20
T;T;T;T
Sift4G
Benign
0.45
T;T;T;T
Polyphen
0.016
B;.;B;.
Vest4
0.15
MutPred
0.41
Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);
MVP
0.69
MPC
0.047
ClinPred
0.16
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.060
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555448900; hg19: chr15-44876452; API