16-89553923-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_003119.4(SPG7):c.2066G>A(p.Arg689His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,496 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 (★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
SPG7
NM_003119.4 missense
NM_003119.4 missense
Scores
7
6
3
Clinical Significance
Conservation
PhyloP100: 9.61
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, 0.779
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.2066G>A | p.Arg689His | missense_variant | 15/17 | ENST00000645818.2 | NP_003110.1 | |
SPG7 | NM_001363850.1 | c.2066G>A | p.Arg689His | missense_variant | 15/18 | NP_001350779.1 | ||
SPG7 | XM_047434537.1 | c.1193G>A | p.Arg398His | missense_variant | 10/13 | XP_047290493.1 | ||
SPG7 | XM_047434540.1 | c.752G>A | p.Arg251His | missense_variant | 7/9 | XP_047290496.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.2066G>A | p.Arg689His | missense_variant | 15/17 | NM_003119.4 | ENSP00000495795 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152240Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000561 AC: 14AN: 249356Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135256
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1460138Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726372
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GnomAD4 genome AF: 0.0000919 AC: 14AN: 152358Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74502
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2022 | 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 expected to disrupt SPG7 protein function. ClinVar contains an entry for this variant (Variation ID: 533738). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. This variant is present in population databases (rs148199060, gnomAD 0.05%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 689 of the SPG7 protein (p.Arg689His). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;D;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;M;.;.;.;.;.;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
REVEL
Pathogenic
Polyphen
1.0
.;.;D;.;.;.;.;.;.
MVP
0.82
MPC
0.86
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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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