chr15-44613499-C-CT

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.3075dupA(p.Glu1026ArgfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,612,946 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SPG11
NM_025137.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 1.34

Publications

16 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 15-44613499-C-CT is Pathogenic according to our data. Variant chr15-44613499-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 1117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPG11	NM_025137.4	MANE Select	c.3075dupA	p.Glu1026ArgfsTer4	frameshift	Exon 17 of 40	NP_079413.3
SPG11	NM_001411132.1		c.3075dupA	p.Glu1026ArgfsTer4	frameshift	Exon 17 of 40	NP_001398061.1
SPG11	NM_001160227.2		c.3075dupA	p.Glu1026ArgfsTer4	frameshift	Exon 17 of 38	NP_001153699.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPG11	ENST00000261866.12	TSL:1 MANE Select	c.3075dupA	p.Glu1026ArgfsTer4	frameshift	Exon 17 of 40	ENSP00000261866.7
SPG11	ENST00000535302.6	TSL:1	c.3075dupA	p.Glu1026ArgfsTer4	frameshift	Exon 17 of 38	ENSP00000445278.2
SPG11	ENST00000427534.6	TSL:1	c.3075dupA	p.Glu1026ArgfsTer4	frameshift	Exon 17 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151918

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:

0.00

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250484

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461028

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726854

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33460

American (AMR)

AF:

0.0000224

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111406

Other (OTH)

AF:

0.0000331

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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:

0.0000132

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74162

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:

41360

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:10Other:1

Jun 25, 2025

Institute of Human Genetics, Heidelberg University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVs1_vs, PP1_s, PM3_mod

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

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.Glu1026ArgfsTer4 variant in SPG11 was identified by our study in two siblings with spastic paraplegia. The p.Glu1026ArgfsTer4 variant in SPG11 has been previously reported in 17 unrelated individuals with hereditary spastic paraplegia 11 (PMID: 29983107, PMID: 35906604, PMID: 35348942, PMID: 32383541, PMID: 18067136, PMID: 19105190, PMID: 19194956, PMID: 20110243, PMID: 27071356, PMID: 27084228, PMID: 28991695) and segregated with disease in 7 affected members from 3 families (PMID: 35348942, PMID: 19194956, PMID: 20110243), but has been identified in 0.01% (3/21626) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs312262752). 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 17 unrelated affected individuals (PMID: 29983107, PMID: 35906604, PMID: 35348942, PMID: 32383541, PMID: 18067136, PMID: 19105190, PMID: 19194956, PMID: 20110243, PMID: 27071356, PMID: 27084228, PMID: 28991695), 8 were homozygotes (PMID: 19194956, PMID: 20110243, PMID: 32383541, PMID: 18067136) and 8 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 29983107, PMID: 35906604, PMID: 35348942, PMID: 32383541, PMID: 19105190, ClinVar ID: 41313; PMID: 27071356 , PMID: 27084228, PMID: 28991695), which increases the likelihood that the p.Glu1026ArgfsTer4 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 1117) 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 1026 and leads to a premature termination codon 4 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 spastic paraplegia 11. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1_Moderate (Richards 2015).

May 23, 2023

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PVS1, PP5

Nov 11, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS4, PM3, PM2_supporting

Paris Brain Institute, Inserm - ICM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 05, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 05, 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.Glu1026Argfs*4) 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 (rs312262752, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive juvenile amyotrophic lateral sclerosis, and hereditary spastic paraplegia (PMID: 18067136, 19105190, 19194956, 20110243, 27071356, 27084228, 28991695). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3076insA, c.3076_3077insA, and c.3075_3076insA,. ClinVar contains an entry for this variant (Variation ID: 1117). 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.

May 22, 2024

Clinical Omics and Informatics (COIN) Unit, Neuroscience Institute, University Of Cape Town

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.0001095 (0.001%; 7/63948 alleles in European Finnish population) and in gnomAD v3.1.2 is 0.00002413 (0.002%; 1/ 41440 alleles in African/African American population) and the variant is absent from an internal database of 1074 control alleles. PP1_moderate: variant segregates with 2 informative meioses in 1 family. PM3_strong: 3 points awarded for 2 homozygous occurrences, 2 observations with pathogenic variant but phase unknown and 1 observation with pathogenic variant confirmed in trans. PVS1_met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:5

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 10, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3, PS4_moderate, PVS1_strong

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG11: PVS1, PM2, PM3, PS4:Moderate

Jan 24, 2023

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28991695, 29983107, 32383541, 27071356, 35254204, 20110243, 18067136)

SPG11-related disorder

Pathogenic:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SPG11 c.3075dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu1026Argfs*4). This variant has been reported in the homozygous or compound heterozygous state in individuals with hereditary spastic paraplegia (see for example, Balicza et al. 2016. PubMed ID: 27084228; Khani et al. 2020. PubMed ID: 32383541; Schneider-Gold et al. 2017. PubMed ID: 28991695). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in SPG11 are expected to be pathogenic. This variant is interpreted as pathogenic.

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

Pathogenic:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Amyotrophic lateral sclerosis type 5

Pathogenic:1

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over