rs752623413

Positions:

• chr16-89556933-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_003119.4(SPG7):​c.2228T>C​(p.Ile743Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,982 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 7.95

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 16-89556933-T-C is Pathogenic according to our data. Variant chr16-89556933-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 215218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.2228T>C	p.Ile743Thr	missense_variant	17/17	ENST00000645818.2	NP_003110.1
SPG7	XM_047434540.1	c.914T>C	p.Ile305Thr	missense_variant	9/9		XP_047290496.1
SPG7	NM_001363850.1	c.*6T>C		3_prime_UTR_variant	18/18		NP_001350779.1
SPG7	XM_047434537.1	c.*6T>C		3_prime_UTR_variant	13/13		XP_047290493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.2228T>C	p.Ile743Thr	missense_variant	17/17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251340 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135900

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000647

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:11 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2022	Variant summary: SPG7 c.2228T>C (p.Ile743Thr) results in a non-conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251340 control chromosomes (gnomAD). c.2228T>C has been reported in the literature in multiple individuals affected with Ataxia/Hereditary Spastic Paraplegia 7 (e.g. van Gassen_2012, Coutelier_2018, Mancini_2019, Bogdanova-Mihaylova_2021). 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. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 09, 2021	- -
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	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed missense variant c.2228T>Cp.Ile743Thr in SPG7 gene has been reported in homozygous/compound heterozygous state in multiple individuals affected with Ataxia/Hereditary Spastic Paraplegia 7 Bogdanova-Mihaylova et al., 2021, Mancini et al., 2019. The p.Ile743Thr variant is reported with 0.005% allele freqeuncy in gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic multiple submissions. Multiple lines of computational evidence Polyphen-probably damaging, SIFT-damaging and Mutation Taster-disease causing predict a damaging effect on protein structure and function for this variant. The amino acid Ile at position 743 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Ile743Thr in SPG7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. However, experimental studies on the pathogenicity of the variant are not available. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.2228T>C in Exon 17 of the SPG7 gene that results in the amino acid substitution p.Ile743Thr was identified. The observed variant has a minor allele frequency of 0.00005/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variant ID 215218). This variant has been previously reported in Pfeffer et al., 2015. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 743 of the SPG7 protein (p.Ile743Thr). This variant is present in population databases (rs752623413, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive primary lateral sclerosis and hereditary spastic paraplegia and adult-onset upper motor neuron syndrome, ataxia, or progressive external ophthalmoplegia (PMID: 18799786, 22964162, 24727571, 25681447, 27123479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215218). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPG7 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -

Spastic ataxia Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jul 12, 2021	- -
Pathogenic, criteria provided, single submitter	research	Tetreault Lab, University of Montreal Hospital Research Centre (CRCHUM)	-	Missense variant of SPG7 predicted that is predicted to disrupt the function of the mitochondrial metalloprotease. The allele frequency is low (gnomAD AF = 4.95e-5) but the variant has previously been reported multiple times (13) through ClinVar for Hereditary Spastic Paraplegia 7, and spastic ataxia. In silico predictions support loss-of-function of the allele (CADD = 25.4; SIFT = 0.99). The metalloprotease is important for mitochondrial function, which correlates with the mitochondrial-related phenotypes of associated condition. Causes Spastic ataxia with episodic manifestations in compound heterozygosity with NM_003119.4 c.1861C>T. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32816195, 34758253, 25681447, 22964162, 18799786, 29023604, 27790088, 29482223, 28362824, 30098094, 24727571, 33300680, 35869996, 34983064, 34445196, 35872528, 27123479) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

SPG7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2023

The SPG7 c.2228T>C variant is predicted to result in the amino acid substitution p.Ile743Thr. This variant has been reported in the compound heterozygous state in multiple individuals with spastic paraplegia, upper motor disease, or ataxia (Brugman et al. 2008. PubMed ID: 18799786; Pfeffer et al. 2015. PubMed ID: 25681447; Coutelier et al. 2018. PubMed ID: 29482223). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89623341-T-C). This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/215218/). Given the evidence, we interpret c.2228T>C (p.Ile743Thr) as pathogenic for autosomal recessive disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;D;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.5	.;.;M;.;.;.;.
PrimateAI	Uncertain	0.63	T
REVEL	Pathogenic	0.86
Polyphen		0.98	.;.;D;.;.;.;.
MutPred		0.76		.;.;Gain of disorder (P = 0.0662);.;.;.;.;
MVP		0.98
MPC		0.80
ClinPred		0.80	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.84

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: rs752623413; hg19: chr16-89623341;