rs768823392

Positions:

• chr16-89546656-AGGAGAGGCG-A
• chr16-89546656-AGGAGAGGCG-AGGAGAGGCGGGAGAGGCG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_003119.4(SPG7):​c.1454_1462del​(p.Arg485_Glu487del) variant causes a splice acceptor, coding sequence change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,606,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SPG7 NM_003119.4 splice_acceptor, coding_sequence
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 U:1 O:1
• Conservation: PhyloP100: 9.91

Genes affected

SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.042713568 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 0 (no position change), new splice context is: tcctcccctggttctggcAGgag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89546656-AGGAGAGGCG-A is Pathogenic according to our data. Variant chr16-89546656-AGGAGAGGCG-A is described in ClinVar as [Pathogenic]. Clinvar id is 411680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89546656-AGGAGAGGCG-A is described in Lovd as [Pathogenic]. Variant chr16-89546656-AGGAGAGGCG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1454_1462del	p.Arg485_Glu487del	splice_acceptor_variant, coding_sequence_variant	11/17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1454_1462del	p.Arg485_Glu487del	splice_acceptor_variant, coding_sequence_variant	11/17		NM_003119.4	ENSP00000495795	P2

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 61 AN: 151660 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251444 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135892

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000349 AC: 507 AN: 1454586 Hom.: 0 AF XY: 0.000338 AC XY: 245 AN XY: 723946

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000565

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000300

GnomAD4 genome AF: 0.000402 AC: 61 AN: 151778 Hom.: 0 Cov.: 31 AF XY: 0.000418 AC XY: 31 AN XY: 74172

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.0000464 Hom.: 0

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:17 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This variant, c.1454_1462del, results in the deletion of 3 amino acid(s) of the SPG7 protein (p.Arg485_Glu487del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768823392, gnomAD 0.08%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 11222789, 22964162, 23065789, 23269439, 23812641, 24466038, 24727571, 26756429, 27165006). 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: 411680). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 13, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	May 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.028%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant is in trans with the other pathogenic variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000411680 / PMID: 11222789 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 13, 2018	- -
Pathogenic, criteria provided, single submitter	research	PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 11, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 15, 2020	DNA sequence analysis of the SPG7 gene demonstrated a nine-base pair deletion in exon 11, c.1454_1462del. This in-frame deletion is predicted to result in the deletion of three amino acid residues, p.Arg485_Glu487del. This in-frame deletion has been described in the homozygous and compound heterozygous states in patients with spastic paraplegia 7 or ataxia (PMIDs: 22964162, 23065789, 11222789). It has been described in the gnomAD population database with a global allele frequency of 0.028% and in the Finnish European subgroup with an allele frequency of 0.080% (rs768823392). Collectively this evidence suggests that this p.Arg485_Glu487del variant is likely pathogenic, however functional studies have not been performed to prove this conclusively -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jun 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2024	Variant summary: SPG7 c.1454_1462delGGCGGGAGA (p.Arg485_Glu487del, also known as c.1450-1_1457del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant allele was found at a frequency of 0.00026 in 251444 control chromosomes. c.1454_1462delGGCGGGAGA has been reported in the literature as a common pathogenic variant in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example, Burguez_2017, van Gassen_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29246610, 22964162). ClinVar contains an entry for this variant (Variation ID: 411680). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SPG7: PS1, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.1450_1458del or c.1450-1_1457del. Pathogenic variants in the SPG7 gene classically exhibit an autosomal recessive mode of disease inheritance, however there is also evidence for autosomal dominant transmission in some families. Consistent with this, some individuals carrying this variant in the heterozygous state display a late onset and/or mild disease (PMID: 11222789, 23065789, 31068484). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2017	The c.1454_1462delGGCGGGAGA (also reported as c.1450_1458del due to alternativenomenclature) in the SPG7 gene has been reported previously in association with spastic paraplegia. Most affectedindividuals were homozygous or compound heterozyogous for SPG7 variants and had typical features of spasticparaplegia 7 (McDermott et al., 2001; van Gassen et al., 2012; Klebe et al., 2012). When reported in theheterozygous state, some individuals had a later onset and milder presentation, sometimes with a cerebellar phenotypewithout spasticity (McDermott et al., 2001; Klebe et al., 2012). The c.1454_1462delGGCGGGAGA variant resultsin an in-frame deletion of three amino acid residues from the resulting protein starting with codon Arginine 485 andending with codon Glutamine 487, denoted p.Arg485_Glu487del. The c.1454_1462delGGCGGGAGA variant wasobserved in approximately 0.15% (12/8254 alleles) in individuals of European ancestry in the NHLBI ExomeSequencing Project. Therefore, we interpret c.1454_1462delGGCGGGAGA variant as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary spastic paraplegia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2020	The p.Arg485_Glu487 del variant in SPG7 is a common pathogenic variant in spastic paraplegia type 7 and it has been reported in the homozygous or compound heterozygous state with another SPG7 pathogenic variant in over 20 individuals with spastic paraplegia (McDermott 2001 PMID: 11222789, van Gassen 2012 PMID: 22964162, Klebe 2012 PMID: 23065789, Pfeffer 2014 PMID: 24727571, van de Warrenburg 2016 PMID: 27165006, Gass 2017 PMID: 29026558, Hewamadduma 2018 PMID: 30533525, Sun 2019 PMID: 29915382, Ngo 2019 PMID: 31692161). This variant also segregated with disease in 4 affected relatives from 4 families (van Gassen PMID: 22964162). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 411680) and has been identified in 0.08% (20/25116) of Finnish chromosomes and 0.04% (55/129114) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of 3 amino acids at position 485 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia type 7. ACMG/AMP Criteria applied: PM3_VeryStrong, PM4, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 01, 2018	- -
Pathogenic, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2016

Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected -

Dysarthria;C0037771:Spastic paraparesis;C0751837:Gait ataxia;C4551583:Cerebral cortical atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Seizure;C0037772:Spastic paraplegia;C0233794:Memory impairment;C0751837:Gait ataxia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Distal spinal muscular atrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Cologne University

Apr 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs768823392; hg19: chr16-89613064;