rs145776296
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_003119.4(SPG7):āc.584A>Gā(p.Tyr195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,612,808 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000086 ( 0 hom., cov: 32)
Exomes š: 0.00012 ( 0 hom. )
Consequence
SPG7
NM_003119.4 missense
NM_003119.4 missense
Scores
2
10
1
Clinical Significance
Conservation
PhyloP100: 3.42
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.767
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.584A>G | p.Tyr195Cys | missense_variant | 4/17 | ENST00000645818.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.584A>G | p.Tyr195Cys | missense_variant | 4/17 | NM_003119.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000856 AC: 13AN: 151840Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251076Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135756
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GnomAD4 exome AF: 0.000117 AC: 171AN: 1460968Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83AN XY: 726698
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GnomAD4 genome ? AF: 0.0000856 AC: 13AN: 151840Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74168
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2017 | p.Tyr195Cys (TAC>TGC), c.584 A>G in exon 4 of the SPG7 gene (NM_003119.2). The Y195C missense substitution in the SPG7 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is semi-conservative in that both Tyrosine and Cysteine are uncharged, polar amino acids; however, the introduction of a Cysteine residue may introduce disulfide bonds in the SPG7 protein and impact the secondary structure of this protein. This change occurs at a position in the SPG7 protein that is not highly conserved. In-silico analyses are not consistent in their predictions as to whether or not Y195C is likely to be damaging to the SPG7 protein. Therefore, based on the currently available information it is unclear whether Y195C is a disease-causing mutation or a rare benign variant. The variant is found in OAPEO-MITOP panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 14, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 21, 2023 | Variant summary: SPG7 c.584A>G (p.Tyr195Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251076 control chromosomes (gnomAD). To our knowledge, no occurrence of c.584A>G in individuals affected with Hereditary Spastic Paraplegia 7 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary spastic paraplegia 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 19, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt SPG7 protein function. ClinVar contains an entry for this variant (Variation ID: 215205). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. This variant is present in population databases (rs145776296, gnomAD 0.01%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 195 of the SPG7 protein (p.Tyr195Cys). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
1.0, 1.0
.;.;D;.;.;.;.;.;.;.;D
Vest4
0.77, 0.78
MVP
0.93
MPC
0.84
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at