NM_025137.4:c.733_734delAT

Variant names:

• chr15-44657229-CAT-C
• rs312262720
• NM_025137.4:c.733_734delAT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025137.4(SPG11):​c.733_734delAT​(p.Met245ValfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,070 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: SPG11 NM_025137.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:2
• Conservation: PhyloP100: -1.17

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 15-44657229-CAT-C is Pathogenic according to our data. Variant chr15-44657229-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44657229-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.733_734delAT	p.Met245ValfsTer2	frameshift_variant	Exon 4 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.733_734delAT	p.Met245ValfsTer2	frameshift_variant	Exon 4 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251452 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135906

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000711 AC: 104 AN: 1461870 Hom.: 0 AF XY: 0.0000646 AC XY: 47 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74354

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:12 Other:1

Feb 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Paris Brain Institute, Inserm - ICM

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

- -

Nov 03, 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.Met245Valfs*2) 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 (rs312262720, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC and juvenile amyotrophic lateral sclerosis (PMID: 17322883, 17717710, 18067136, 18079167, 18332254, 18835492, 19105190, 19438933, 20110243, 22175763, 22237444, 22696581, 24833714, 27071356). ClinVar contains an entry for this variant (Variation ID: 1112). 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. -

Mar 17, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 15, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001112 /PMID: 17322883 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift deletion p.M245Vfs*2 in SPG11 (NM_025137.4) has been previously reported in many individuals affected with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC (Stevanin et al, 2007;Del Bo et al. 2007). This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 2 residues until a stop codon is reached. The p.M245Vfs*2 variant is a loss of function variant in the gene SPG11, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Met245ValfsTer2 variant in SPG11 was identified by our study in the compound heterozygous state, along with another pathogenic variant, in two siblings with spastic paraplegia. The presence of this variant in combination with a reported pathogenic variant and in an individual with spastic paraplegia increases the likelihood that the p.Met245ValfsTer2 variant is pathogenic. The p.Met245ValfsTer2 variant in SPG11 has been well-reported in the literature. This variant has been reported in greater than 22 individuals from Italy, Japan, France, Tunisia, Sicily, Korea, Spain, China, and Portugal with spastic paraplegia in the homozygous and compound heterozygous state, segregated with disease in 12 affected relatives from 5 families (PMID: 17717710, 20110243, 17322883, 18079167, 22175763, 18332254, 24833714, 22696581, 22237444, 18067136, 18835492), but has been identified in 0.006133% (17/277208) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs312262720). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1112). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 245 and leads to a premature termination codon 2 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 spastic paraplegia. In summary, the p.Met245ValfsTer2variant is pathogenic based off of our findings, multiple reports of pathogenicity in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PVS1, PM3, PP1_Moderate (Richards 2015). -

Jan 01, 2018

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The observed variant c.733_734delAT (p.M245Vfs) is not reported in The 1000 Genomes database and its minor allele frequency in ExAC database is 0.0001071. The in silico prediction for the variant is pathogenic by MutationTaster2. -

Jan 28, 2025

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: PVS1, PM2_Supporting, PM3_VeryStrong -

Apr 23, 2024

University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant is classified as pathogenic because it is a frameshift variant identified in the homozygote state in a single case. ClinVar contains an entry for this variant (Variation ID: 1112), it’s classified as pathogenic. This variant is not reported in the 1000 Genomes Project but is present at a low frequency in the gnomAD database [AF = 6.49e-5]. This is a recurrent variant associated with the following publication (PMID: 17322883, 18067136, 18332254, 22175763, 22696581, 27071356, 30778698, 36524102). -

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Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Pathogenic:3

Aug 11, 2022

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.733_734delAT (p.Met245ValfsX2) 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. Truncations downstream of this position are associated with Spastic Paraplegia in HGMD. The variant allele was found at a frequency of 6.8e-05 in 251452 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (6.8e-05 vs 0.0011). c.733_734delAT has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia (examples: Boukhris_2009 and Stevanin_2008). These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=7) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2X Pathogenic:2

Jan 21, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormal central motor function Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jan 03, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733_734delAT (p.M245Vfs*2) alteration, located in coding exon 4 of the SPG11 gene, results from a deletion of 2 nucleotides from position 733 to 734, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the c.733_734delAT alteration was observed in 0.006% (18/282852) of total alleles studied. In multiple individuals with spastic paraplegia with thin corpus callosum, this alteration has been detected in the homozygous state or in conjunction with a second disease-causing allele (Stevanin, 2007; Boukhris, 2008; Pensato, 2014; Dong, 2018; Wei, 2019). This alteration was also identified in a patient meeting diagnostic criteria for amyotrophic lateral sclerosis (ALS) and a brain MRI which was negative for thin corpus callosum and white matter abnormalities; this individual was also heterozygous for a nonsense variant in SPG11 (Orlacchio, 2010). Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Pathogenic:1

Mar 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 02, 2021

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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17717710, 18332254, 20110243, 22175763, 17322883, 18067136, 27071356, 31227335, 31289639, 31969655, 29980238, 31589614) -

Amyotrophic lateral sclerosis type 5 Pathogenic:1

Feb 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5 Other:1

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 05-07-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs312262720; hg19: chr15-44949427;