rs312262728

Variant summary

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

The NM_025137.4(SPG11):​c.1492C>T​(p.Gln498*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q498Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SPG11
NM_025137.4 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.04
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 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 15-44648976-G-A is Pathogenic according to our data. Variant chr15-44648976-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41399.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.1492C>T p.Gln498* stop_gained Exon 7 of 40 ENST00000261866.12 NP_079413.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPG11ENST00000261866.12 linkc.1492C>T p.Gln498* stop_gained Exon 7 of 40 1 NM_025137.4 ENSP00000261866.7 Q96JI7-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251250
AF XY:
0.00000736
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461624
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33474
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44722
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26130
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39676
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86252
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53414
Gnomad4 NFE exome
AF:
0.00000270
AC:
3
AN:
1111808
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60380
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:4
Feb 07, 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.Gln498*) 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 (rs312262728, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 20971220, 24833714). ClinVar contains an entry for this variant (Variation ID: 41399). For these reasons, this variant has been classified as Pathogenic. -

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

- -

Jul 22, 2021
Genome-Nilou Lab
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 25, 2023
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

The homozygous p.Gln498Ter variant in SPG11 was identified by our study in two siblings with spastic paraplegia. The p.Gln498Ter variant in SPG11 has been reported in 2 unrelated individuals with hereditary spastic paraplegia 11 (PMID: 20971220, PMID: 24833714) and segregated with disease in five affected relatives from one family (PMID: 20971220), but has been identified in 0.002% (2/113568) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs312262728). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 2 unrelated affected individuals (PMID: 20971220, PMID: 24833714), one was a homozygote (PMID: 20971220) and one was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 24833714, ClinVar Variation ID: 1180685), which increases the likelihood that the p.Gln498Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 41399) and has been interpreted as pathogenic by the Genome-Nilou Lab, the ​​CeGaT Center for Human Genetics Tuebingen, and GeneReviews. This nonsense variant leads to a premature termination codon at position 498, which is predicted to lead to a truncated or absent protein. Loss of function of the SPG11 gene is an established disease mechanism in autosomal recessive SPG11-related neurologic disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia 11. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong, PP1_Moderate (Richards 2015). -

not provided Pathogenic:1
Jan 01, 2018
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.92
GERP RS
5.8
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs312262728; hg19: chr15-44941174; API