chr15-44584222-GCT-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025137.4(SPG11):​c.5456_5457delAG​(p.Glu1819AlafsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

SPG11
NM_025137.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.410

Publications

5 publications found
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]
SPG11 Gene-Disease associations (from GenCC):
  • hereditary spastic paraplegia 11
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
  • amyotrophic lateral sclerosis type 5
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • Charcot-Marie-Tooth disease axonal type 2X
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
  • juvenile amyotrophic lateral sclerosis
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-44584222-GCT-G is Pathogenic according to our data. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44584222-GCT-G is described in CliVar as Pathogenic. Clinvar id is 41368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPG11NM_025137.4 linkc.5456_5457delAG p.Glu1819AlafsTer10 frameshift_variant Exon 30 of 40 ENST00000261866.12 NP_079413.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPG11ENST00000261866.12 linkc.5456_5457delAG p.Glu1819AlafsTer10 frameshift_variant Exon 30 of 40 1 NM_025137.4 ENSP00000261866.7 Q96JI7-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251418
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000896
AC:
131
AN:
1461888
Hom.:
0
AF XY:
0.0000866
AC XY:
63
AN XY:
727248
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000114
AC:
127
AN:
1112006
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
9
18
28
37
46
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41438
American (AMR)
AF:
0.00
AC:
0
AN:
15266
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000882
AC:
6
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.554
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000491
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:3
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu1819Alafs*10) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs749819954, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 18337587; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41368). For these reasons, this variant has been classified as Pathogenic. -

-
Genome-Nilou Lab
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 31, 2013
GeneReviews
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:curation

- -

Inborn genetic diseases Pathogenic:1
Feb 03, 2021
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.5456_5457delAG pathogenic mutation, located in coding exon 30 of the SPG11 gene, results from a deletion of two nucleotides at nucleotide positions 5456 to 5457, causing a translational frameshift with a predicted alternate stop codon (p.E1819Afs*10). This mutation was detected in a compound heterozygous state with other truncating alterations in SPG11 in two siblings and one additional unrelated individual, all of whom had phenotypes consistent with hereditary spastic paraplegia (Paisan-Ruiz C et al. Neurology, 2008 Apr;70:1384-9; Kara E et al. Brain, 2016 07;139:1904-18). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Pathogenic:1
Apr 10, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary spastic paraplegia Pathogenic:1
Mar 01, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:1
Jul 25, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PP1, PM2, PM3_very_strong, PVS1 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.41
Mutation Taster
=1/199
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs312262764; hg19: chr15-44876420; API