rs132630282
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The ENST00000621218.5(PLP1):c.544A>C(p.Thr182Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T182T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 22)
Consequence
PLP1
ENST00000621218.5 missense
ENST00000621218.5 missense
Scores
7
4
3
Clinical Significance
Conservation
PhyloP100: 2.54
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000621218.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant X-103787888-A-C is Pathogenic according to our data. Variant chrX-103787888-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 11079.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-103787888-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLP1 | NM_000533.5 | c.544A>C | p.Thr182Pro | missense_variant | 4/7 | ENST00000621218.5 | NP_000524.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLP1 | ENST00000621218.5 | c.544A>C | p.Thr182Pro | missense_variant | 4/7 | 1 | NM_000533.5 | ENSP00000484450 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ExAC
AF:
AC:
8
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Pelizaeus-Merzbacher disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1992 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Polyphen
D;D;P
Vest4
MutPred
Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);.;
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