rs757130394
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_014946.4(SPAST):c.1417C>A(p.Gln473Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,613,012 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 2 hom. )
Consequence
SPAST
NM_014946.4 missense
NM_014946.4 missense
Scores
2
5
12
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 7.00
Genes affected
SPAST (HGNC:11233): (spastin) This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein 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. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4. [provided by RefSeq, May 2018]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP5
Variant 2-32137112-C-A is Pathogenic according to our data. Variant chr2-32137112-C-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.10226151). . Strength limited to SUPPORTING due to the PP5.
BS2
High AC in GnomAdExome4 at 56 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPAST | NM_014946.4 | c.1417C>A | p.Gln473Lys | missense_variant | 12/17 | ENST00000315285.9 | NP_055761.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPAST | ENST00000315285.9 | c.1417C>A | p.Gln473Lys | missense_variant | 12/17 | 1 | NM_014946.4 | ENSP00000320885 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251190Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135748
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GnomAD4 exome AF: 0.0000383 AC: 56AN: 1460846Hom.: 2 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 726836
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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ClinVar
Not reported inComputational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;T;.;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;N;.;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;.;N;.;.;.;.;.
REVEL
Uncertain
Sift
Benign
T;.;T;.;.;.;.;.
Sift4G
Benign
T;T;T;.;.;.;.;.
Polyphen
B;B;.;.;.;.;.;.
Vest4
MutPred
Gain of ubiquitination at Q473 (P = 0.0121);Gain of ubiquitination at Q473 (P = 0.0121);.;.;.;.;.;.;
MVP
MPC
ClinPred
T
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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