rs312262770

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_025137.4(SPG11):c.5769delT(p.Ser1923ArgfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S1923S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SPG11
NM_025137.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.585

Publications

11 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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-44583910-TA-T is Pathogenic according to our data. Variant chr15-44583910-TA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 41327.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.5769delT	p.Ser1923ArgfsTer28	frameshift_variant	Exon 30 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.5769delT	p.Ser1923ArgfsTer28	frameshift_variant	Exon 30 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251404

AF XY:

0.0000810

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:

0.0000274

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Oct 20, 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.Ser1923Argfs*28) 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 (rs312262770, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (HSP) (PMID: 18079167, 18337587, 22246010, 27217339). It has also been observed to segregate with disease in related individuals. This variant is also known as p.S1923RfsX1950. ClinVar contains an entry for this variant (Variation ID: 41327). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Paris Brain Institute, Inserm - ICM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia

Pathogenic:2

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SPG11 c.5769delT (p.Ser1923ArgfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.2e-05 in 251404 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (5.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.5769delT has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia, Type 11 (example: Paisan-Ruiz_2008). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 18337587). ClinVar contains an entry for this variant (Variation ID: 41327). Based on the evidence outlined above, the variant was classified as pathogenic.

not provided

Pathogenic:2

May 03, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift 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; This variant is associated with the following publications: (PMID: 31281085, 18337587, 20301389, 23439843, 27544499, 22246010, 18079167, 27457812, 21779300, 32383541, 26582918, 27535533)

Dec 05, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Jul 15, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5769delT pathogenic mutation, located in coding exon 30 of the SPG11 gene, results from a deletion of one nucleotide at nucleotide position 5769, causing a translational frameshift with a predicted alternate stop codon (p.S1923Rfs*28). This alteration has been detected in the homozygous state, or in conjunction with another SPG11 truncating alteration, in multiple unrelated individuals with SPG11-related neurologic disorders (Khani M et al. Mol Genet Genomic Med, 2020 07;8:e1240; Zulfiqar S et al. J Clin Neurosci, 2019 Sep;67:19-23; Kara E et al. Brain, 2016 07;139:1904-18; Paisan-Ruiz C et al. Neurology, 2008 Apr;70:1384-9; Wakil SM et al. Neurosciences (Riyadh), 2012 Jan;17:48-52). 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.

Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:1

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.Ser1923ArgfsTer28 variant in SPG11 was identified by our study in one individual with Charcot-Marie Tooth disease. The p.Ser1923ArgfsTer28 variant in SPG11 has been previously reported in 3 unrelated individuals with SPG11-related neurologic disease (PMID: 27457812, PMID: 18337587, PMID: 18079167) and segregated with disease in 4 affected relatives from one family (PMID: 18337587), but has been identified in 0.04% (13/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs949342628). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. These 3 affected unrelated individuals were homozygotes (PMID: 27457812, PMID: 18337587, PMID: 18079167), which increases the likelihood that the p.Ser1923ArgfsTer28 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 41327) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 1923 and leads to a premature termination codon 28 amino acids downstream. This alteration is then 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 SPG11-related neurologic disease. ACMG/AMP Criteria applied: PVS1, PM3, PP1_Moderate (Richards 2015).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.58

Mutation Taster

=1/199

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over