chr15-44565975-C-T

Variant summary

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

The NM_025137.4(SPG11):​c.6878G>A​(p.Arg2293Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,613,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2293W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 2.35
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]

Genome browser will be placed here

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=0.14875314).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPG11NM_025137.4 linkuse as main transcriptc.6878G>A p.Arg2293Gln missense_variant 38/40 ENST00000261866.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPG11ENST00000261866.12 linkuse as main transcriptc.6878G>A p.Arg2293Gln missense_variant 38/401 NM_025137.4 Q96JI7-1

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000115
AC:
29
AN:
251124
Hom.:
0
AF XY:
0.0000958
AC XY:
13
AN XY:
135768
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000278
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000200
AC:
293
AN:
1461672
Hom.:
1
Cov.:
32
AF XY:
0.000198
AC XY:
144
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000525
Gnomad4 NFE exome
AF:
0.000225
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000281
Hom.:
0
Bravo
AF:
0.000159
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 19, 2021Reported previously in a patient with Parkinson's disease, however further clinical information was not provided (Ghani et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29119460, 25174650) -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024SPG11: PM2 -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Hereditary spastic paraplegia 11 Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 15, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2293 of the SPG11 protein (p.Arg2293Gln). This variant is present in population databases (rs201721414, gnomAD 0.04%). This missense change has been observed in individual(s) with Parkinson's disease (PMID: 25174650). This variant is also known as p.Arg2180Gln. ClinVar contains an entry for this variant (Variation ID: 522343). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterOct 09, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou Lab-- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 11, 2024Variant summary: SPG11 c.6878G>A (p.Arg2293Gln) results in a conservative amino acid change located in the Spatacsin, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251124 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.6878G>A has been reported in the literature in an individual affected with Parkinson's disease (Ghani_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia, Type 11. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25174650). ClinVar contains an entry for this variant (Variation ID: 522343). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 30, 2023The c.6878G>A (p.R2293Q) alteration is located in exon 38 (coding exon 38) of the SPG11 gene. This alteration results from a G to A substitution at nucleotide position 6878, causing the arginine (R) at amino acid position 2293 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Amyotrophic lateral sclerosis type 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou Lab-- -
Charcot-Marie-Tooth disease axonal type 2X Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou Lab-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.077
T;.;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Uncertain
0.16
D
MutationAssessor
Uncertain
2.3
M;.;.
MutationTaster
Benign
1.0
D;D;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.66
N;N;N
REVEL
Uncertain
0.33
Sift
Benign
0.049
D;T;T
Sift4G
Uncertain
0.010
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.33
MVP
0.78
MPC
0.21
ClinPred
0.11
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs201721414; hg19: chr15-44858173; COSMIC: COSV55992740; COSMIC: COSV55992740; API