NM_025137.4:c.2716delC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong
The NM_025137.4(SPG11):c.2716delC (p.Gln906SerfsTer15) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000041 (AC=6) in the gnomAD database across 1,461,806 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000305. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SPG11
NM_025137.4 frameshift
NM_025137.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.61
Publications
1 publications found
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 11Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Illumina
- amyotrophic lateral sclerosis type 5Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Charcot-Marie-Tooth disease axonal type 2XInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- juvenile amyotrophic lateral sclerosisInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_025137.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Classification was made for transcript
Our verdict: Pathogenic. The variant received 14 points.
PVS1
Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 15 of 40) at amino acid 906 of 2443, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~919 amino acids (1524 amino acids lost).
PM2
Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000305 — very rare for AR gene (threshold 0.001) — PM2 moderate.
PP5
ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_025137.4. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SPG11 | MANE Select | c.2716delC | p.Gln906SerfsTer15 | frameshift | Exon 15 of 40 | NP_079413.3 | |||
| SPG11 | c.2716delC | p.Gln906SerfsTer15 | frameshift | Exon 15 of 40 | NP_001398061.1 | A0A804HID9 | |||
| SPG11 | c.2716delC | p.Gln906SerfsTer15 | frameshift | Exon 15 of 38 | NP_001153699.1 | Q96JI7-3 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SPG11 | TSL:1 MANE Select | c.2716delC | p.Gln906SerfsTer15 | frameshift | Exon 15 of 40 | ENSP00000261866.7 | Q96JI7-1 | ||
| SPG11 | TSL:1 | c.2716delC | p.Gln906SerfsTer15 | frameshift | Exon 15 of 38 | ENSP00000445278.2 | Q96JI7-3 | ||
| SPG11 | TSL:1 | c.2716delC | p.Gln906SerfsTer15 | frameshift | Exon 15 of 37 | ENSP00000396110.2 | F8W8Y5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251404 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
251404
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727212 show subpopulations
GnomAD4 exome
AF:
AC:
6
AN:
1461806
Hom.:
Cov.:
31
AF XY:
AC XY:
3
AN XY:
727212
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33476
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26130
East Asian (EAS)
AF:
AC:
0
AN:
39686
South Asian (SAS)
AF:
AC:
6
AN:
86254
European-Finnish (FIN)
AF:
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111958
Other (OTH)
AF:
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
Hereditary spastic paraplegia 11 (5)
2
-
-
not provided (2)
1
-
-
Hereditary spastic paraplegia (1)
1
-
-
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs312262747 ;
hg19: chr15-44912505;