rs150571352

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

Scores

1
12
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 4.81
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 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
SPG11NM_025137.4 linkuse as main transcriptc.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
SPG11ENST00000261866.12 linkuse as main transcriptc.7132T>C p.Phe2378Leu missense_variant 39/401 NM_025137.4 ENSP00000261866.7 Q96JI7-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000203
AC:
51
AN:
251000
Hom.:
0
AF XY:
0.000206
AC XY:
28
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.0000621
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000264
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.000133
AC:
195
AN:
1461702
Hom.:
0
Cov.:
31
AF XY:
0.000149
AC XY:
108
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000103
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000167
Hom.:
0
Bravo
AF:
0.000140
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 06, 2022This 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 submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityJul 11, 2022This 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 submitterclinical testingAmbry GeneticsNov 27, 2023The 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 02, 2024- -
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJan 14, 2020- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundMar 27, 2023- -
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -
Amyotrophic lateral sclerosis type 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMay 05, 2020This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 05, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.066
T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.082
D
MetaRNN
Uncertain
0.65
D;D
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Uncertain
2.2
M;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.0
N;N
REVEL
Uncertain
0.34
Sift
Uncertain
0.0080
D;T
Sift4G
Uncertain
0.026
D;D
Polyphen
1.0
D;.
Vest4
0.81
MutPred
0.30
Gain of disorder (P = 0.0827);.;
MVP
0.76
MPC
0.18
ClinPred
0.10
T
GERP RS
5.0
Varity_R
0.15
gMVP
0.49

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: rs150571352; hg19: chr15-44856764; API