rs312262759

Positions:

• chr15-44596208-CTT-C

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.4307_4308delAA​(p.Gln1436fs) 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 1,614,168 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 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SPG11 NM_025137.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 0.157

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 (HGNC:):

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 15-44596208-CTT-C is Pathogenic according to our data. Variant chr15-44596208-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 41315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44596208-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.4307_4308delAA	p.Gln1436fs	frameshift_variant	25/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.4307_4308delAA	p.Gln1436fs	frameshift_variant	25/40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251420 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135874

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461882 Hom.: 0 AF XY: 0.0000261 AC XY: 19 AN XY: 727244

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152286 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74454

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift deletion p.Q1436Rfs*7 in SPG11 (NM_025137.4) has been reported to ClinVar as Pathogenic. This variant has been observed in individuals affected with autosomal recessive hereditary spastic paraplegia and to segregate with disease in a family (Stevanin G et al, 2008; Novarino G et al, 2014). The p.Q1436Rfs*7 variant is observed in 1/16,256 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 7 residues until a stop codon is reached. The gene SPG11 has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 3.29. The p.Q1436Rfs*7 variant is a loss of function variant in the gene SPG11, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_079413.3:p.L68Ffs*2 and 156 others. There are 83 downstream pathogenic loss of function variants, with the furthest variant being 952 residues downstream of the variant p.Q1436Rfs*7. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 10, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change creates a premature translational stop signal (p.Gln1436Argfs*7) 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 (rs312262759, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 18079167, 24482476). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41315). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 25, 2021	- -
Pathogenic, no assertion criteria provided	research	Section for Clinical Neurogenetics, University of Tübingen	Aug 01, 2019	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2023	PP1_strong, PM2_moderate, PM3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2023	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: 18586399, 30081747, 19105190, 24482476, 29980238, 26374131, 24833714, 18079167, 31589614, 32214227, 33098801, 33619735, 35872528) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The c.4307_4308delAA (p.Q1436Rfs*7) alteration, located in exon 25 (coding exon 25) of the SPG11 gene, consists of a deletion of 2 nucleotides from position 4307 to 4308, causing a translational frameshift with a predicted alternate stop codon after 7 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 gnomAD, the c.4307_4308delAA (p.Q1436Rfs*7) alteration has an overall frequency of 0.004% (10/282800) total alleles studied. The highest observed frequency was 0.012% (3/24962) of African alleles. This alteration has been detected in the homozygous state or in conjunction with a second disease-causing allele in multiple individuals with SPG11-related neurologic disorders (Stevanin, 2008; Lynch, 2016; Pensato, 2014; Denora, 2009; Chen, 2008; Hengel 2020; Zech 2020; Shi 2022; Utz 2022; Dosi, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

Charcot-Marie-Tooth disease axonal type 2X Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs312262759; hg19: chr15-44888406;