rs312262709

Variant names:

Variant summary

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

The NM_025137.4(SPG11):c.267G>A(p.Trp89*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,804 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SPG11
NM_025137.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 4.81

Publications

15 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

SPG11 links:

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 15-44660607-C-T is Pathogenic according to our data. Variant chr15-44660607-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 41294.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
SPG11	NM_025137.4 link	c.267G>A	p.Trp89*	stop_gained	Exon 2 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 link	c.267G>A	p.Trp89*	stop_gained	Exon 2 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251148

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111970

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:5Other:1

Sep 23, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous nonsense variation in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 was detected . This variant has not been reported in the 1000 genomes and gnomAD databases . The in silico prediction# of the variant is damaging by MutationTaster2. The reference codon is conserved across species. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been observed to be homozygous or in combination with another SPG11 variant in individuals affected with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (Orlacchio A et.al.,2010). This variant has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003982% is reported in gnomAD. Loss-of-function variants in SPG11 are known to be pathogenic. The nucleotide change in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -

Sep 21, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary spastic paraplegia 11 (HSP; MONDO#0011445). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals, both as homozygotes and compound heterozygotes, with HSP (PMID: 35906604) and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 13, 2023

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.Trp89*) 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 (rs312262709, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (PMID: 18067136, 20110243, 27217339). ClinVar contains an entry for this variant (Variation ID: 41294). 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:2

Mar 10, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18717728, 26971897, 30574063, 20110243, 18067136) -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG11: PVS1, PM2, PM3 -

Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:2

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been reported in homozygous and compound heterozygous state in individuals affected with Charcot-Marie-Tooth disease (Montecchiani C et al. 2016). The p.Trp89Ter variant has allele frequency 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.267G>A in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in SPG11 are known to be pathogenic (Denora PS et al. 2009). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -

Mar 02, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous nonsense variant in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 (p.Trp89Ter) was detected. The observed variant has previously been reported in patients affected with hereditary spastic paraplegia [PMID: 27217339]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. -

Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:1

Apr 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 5

Pathogenic:1

Feb 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.94

PhyloP100

4.8

Vest4

0.67

GERP RS

5.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over