rs777638594
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_003119.4(SPG7):c.445G>A(p.Ala149Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000342 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
SPG7
NM_003119.4 missense
NM_003119.4 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 6.65
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 | UniProt |
---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.445G>A | p.Ala149Thr | missense_variant | 4/17 | ENST00000645818.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.445G>A | p.Ala149Thr | missense_variant | 4/17 | NM_003119.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251240Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135792
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461644Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727112
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
Bravo
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2
ALSPAC
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0
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
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 | Jun 08, 2017 | The A149T variant in the SPG7 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A149T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A149T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Alanine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A149T as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 13, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;.;.;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;L;.;.;.;.;.;.;.;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;.;.;.;.;.;.;N;N
REVEL
Uncertain
Sift
Benign
.;.;.;.;.;.;.;.;.;T;T
Sift4G
Benign
.;.;.;.;.;.;.;.;.;T;T
Polyphen
0.66, 0.83
.;.;P;.;.;.;.;.;.;.;P
Vest4
0.32, 0.34
MutPred
0.48
.;.;Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP
0.78
MPC
0.36
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at