rs369227537

Variant names:

Variant summary

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

The NM_003119.4(SPG7):c.1672A>T(p.Lys558*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,612,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SPG7
NM_003119.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 7.39

Publications

7 publications found

Variant links:

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]

SPG7 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 7
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPG7 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 16-89550502-A-T is Pathogenic according to our data. Variant chr16-89550502-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SPG7	NM_003119.4 link	c.1672A>T	p.Lys558*	stop_gained	Exon 13 of 17	ENST00000645818.2	NP_003110.1
SPG7	NM_001363850.1 link	c.1672A>T	p.Lys558*	stop_gained	Exon 13 of 18		NP_001350779.1
SPG7	XM_047434537.1 link	c.799A>T	p.Lys267*	stop_gained	Exon 8 of 13		XP_047290493.1
SPG7	XM_047434540.1 link	c.358A>T	p.Lys120*	stop_gained	Exon 5 of 9		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.1672A>T	p.Lys558*	stop_gained	Exon 13 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

250930

AF XY:

0.000147

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:

0.0000473

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000154

AC:

225

AN:

1460152

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

726420

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000200

AC:

222

AN:

1111016

Other (OTH)

AF:

0.0000166

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.0000920

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

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:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000162

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7

Pathogenic:6Other:1

Paris Brain Institute, Inserm - ICM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 13, 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.Lys558*) in the SPG7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162). This variant is present in population databases (rs369227537, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 22964162, 24727571, 26756429). ClinVar contains an entry for this variant (Variation ID: 188276). For these reasons, this variant has been classified as Pathogenic. -

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2019

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GenomeConnect - Brain Gene Registry

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Pathogenic and reported on 11-08-2022 by Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO:0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (37 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in compound heterozygous and homozygous individuals with spastic paraplegia. Some of these individuals also had ataxia (ClinVar, PMID: 22964162). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:5

May 20, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense 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: 27858775, 24727571, 26756429, 22964162, 31589614, 37121968, 28362824, 34983064, 29057857) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2022

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). 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. -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG7: PVS1, PM3:Strong, PM2 -

Inborn genetic diseases

Pathogenic:1

Aug 17, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1672A>T (p.K558*) alteration, located in exon 13 (coding exon 13) of the SPG7 gene, consists of a A to T substitution at nucleotide position 1672. This changes the amino acid from a lysine (K) to a stop codon at amino acid position 558. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the homozygous and compound heterozygous states in multiple individuals with features of SPG7-related spastic paraplegia (Iqbal, 2017; Pfeffer, 2014; Rydning, 2016; Taylor, 2019; van Gassen, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Mitochondrial disease

Pathogenic:1

Apr 07, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

SPG7-related disorder

Pathogenic:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SPG7 c.1672A>T variant is predicted to result in premature protein termination (p.Lys558*). This variant has been reported to be causative for spastic paraplegia (van Gassen et al. 2012. PubMed ID: 22964162; Bhattacharjee et al. 2017. PubMed ID: 29057857). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in SPG7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary spastic paraplegia

Pathogenic:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary ataxia

Pathogenic:1

Apr 17, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.4

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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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