rs745459731
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_003119.4(SPG7):c.1175G>A(p.Ser392Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SPG7
NM_003119.4 missense
NM_003119.4 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 6.44
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.1175G>A | p.Ser392Asn | missense_variant | 9/17 | ENST00000645818.2 | NP_003110.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.1175G>A | p.Ser392Asn | missense_variant | 9/17 | NM_003119.4 | ENSP00000495795 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248352Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135234
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461262Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726926
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GnomAD4 genome Cov.: 33
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33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 16, 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: 465171). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. This variant is present in population databases (rs745459731, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 392 of the SPG7 protein (p.Ser392Asn). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 04, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;.;.;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;N;.;.;.;.;.;N
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;.;.;.;.;.;.;.;N
REVEL
Uncertain
Sift
Benign
.;.;.;.;.;.;.;.;T
Sift4G
Benign
.;.;.;.;.;.;.;.;T
Polyphen
0.13, 0.18
.;.;B;.;.;.;.;.;B
Vest4
0.81
MutPred
0.62
.;.;Loss of phosphorylation at S392 (P = 0.0283);Loss of phosphorylation at S392 (P = 0.0283);Loss of phosphorylation at S392 (P = 0.0283);Loss of phosphorylation at S392 (P = 0.0283);Loss of phosphorylation at S392 (P = 0.0283);.;Loss of phosphorylation at S392 (P = 0.0283);
MVP
0.83
MPC
0.74
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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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