rs864622507

Variant names:

• chr16-89553103-C-T
• rs864622507
• NM_003119.4:c.1904C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_003119.4(SPG7):​c.1904C>T​(p.Ser635Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,038 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S635S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 7.84
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 16-89553103-C-T is Pathogenic according to our data. Variant chr16-89553103-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220393.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1904C>T	p.Ser635Leu	missense_variant	Exon 14 of 17	ENST00000645818.2	NP_003110.1
SPG7	NM_001363850.1	c.1904C>T	p.Ser635Leu	missense_variant	Exon 14 of 18		NP_001350779.1
SPG7	XM_047434537.1	c.1031C>T	p.Ser344Leu	missense_variant	Exon 9 of 13		XP_047290493.1
SPG7	XM_047434540.1	c.590C>T	p.Ser197Leu	missense_variant	Exon 6 of 9		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1904C>T	p.Ser635Leu	missense_variant	Exon 14 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460038 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726174

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.0000225 AC: 1 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111310

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:3

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SPG7 c.1904C>T (p.Ser635Leu) results in a non-conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245664 control chromosomes (gnomAD). c.1904C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Hereditary Spastic Paraplegia and cerebellar ataxia (e.g. Elleuch_2006, Hewamadduma_2018, Sun_2019, Mao_2020) and was shown to segregate with disease in at least one family (Mao_2020). 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 07, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 635 of the SPG7 protein (p.Ser635Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16534102, 29915382, 30533525, 32002796; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 220393). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:3

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16534102, 28294470, 30533525, 32002796, 38374194, 22571692, 29915382) -

May 22, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SPG7-related disorder Pathogenic:1

Oct 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SPG7 c.1904C>T variant is predicted to result in the amino acid substitution p.Ser635Leu. This variant has been reported with another SPG7 variant in multiple unrelated individuals with hereditary spastic paraplegia (HSP) and cerebellar ataxia (Elleuch et al. 2006. PubMed ID: 16534102; Hewamadduma et al. 2018. PubMed ID: 30533525; Sun et al. 2018. PubMed ID: 29915382). This variant has also been documented in the homozygous state in two affected siblings; segregation analysis revealed that both unaffected parents were heterozygous carriers for this variant (Mao et al. 2020. PubMed ID: 32002796). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;D;.;.;.;.;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	2.0	.;.;M;.;.;.;.;.;.
PhyloP100		7.8
PrimateAI	Benign	0.45	T
REVEL	Uncertain	0.49
Polyphen		0.35	.;.;B;.;.;.;.;.;.
MutPred		0.77		.;.;Loss of disorder (P = 0.0283);.;.;.;Loss of disorder (P = 0.0283);.;.;
MVP		0.91
MPC		0.32
ClinPred		0.96	D
GERP RS		5.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.5
Varity_R		0.66
gMVP		0.95
Mutation Taster		=22/78	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864622507; hg19: chr16-89619511;