chr15-44570550-GC-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.6451delG​(p.Ala2151ProfsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 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: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPG11
NM_025137.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 7.83

Publications

3 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 15-44570550-GC-G is Pathogenic according to our data. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44570550-GC-G is described in CliVar as Pathogenic. Clinvar id is 41344.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.6451delG p.Ala2151ProfsTer22 frameshift_variant Exon 34 of 40 ENST00000261866.12 NP_079413.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPG11ENST00000261866.12 linkc.6451delG p.Ala2151ProfsTer22 frameshift_variant Exon 34 of 40 1 NM_025137.4 ENSP00000261866.7 Q96JI7-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251098
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461846
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727218
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53396
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112004
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:2Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Mar 01, 2024
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.Ala2151Profs*22) 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 (rs312262779, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 17322883). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41344). 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

- -

not provided Pathogenic:1
Feb 21, 2018
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.8
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs312262779; hg19: chr15-44862748; API