rs1556270478
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_000533.5(PLP1):c.687A>C(p.Lys229Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 23)
Consequence
PLP1
NM_000533.5 missense
NM_000533.5 missense
Scores
2
4
8
Clinical Significance
Conservation
PhyloP100: 1.07
Publications
0 publications found
Genes affected
PLP1 (HGNC:9086): (proteolipid protein 1) This gene encodes a transmembrane proteolipid protein that is the predominant component of myelin. The encoded protein may play a role in the compaction, stabilization, and maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival. Mutations in this gene cause Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Alternatively splicing results in multiple transcript variants, including the DM20 splice variant. [provided by RefSeq, Feb 2015]
RAB9B (HGNC:14090): (RAB9B, member RAS oncogene family) This gene encodes a member of a subfamily of RAS small guanosine triphosphate (GTP)-binding proteins that regulate membrane trafficking. The encoded protein may be involved in endosome-to-Golgi transport. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000533.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 2, Pelizeaus-Merzbacher spectrum disorder, Pelizaeus-Merzbacher disease in female carriers, null syndrome, Pelizaeus-Merzbacher disease, transitional form, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease, connatal form.
BP4
Computational evidence support a benign effect (MetaRNN=0.39244154).
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Jan 22, 2017
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
DEOGEN2
Uncertain
D;D;.
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.
PhyloP100
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T
Polyphen
B;B;B
Vest4
MutPred
Loss of methylation at K229 (P = 0.0073);Loss of methylation at K229 (P = 0.0073);.;
MVP
ClinPred
D
GERP RS
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
Publications
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