rs1556267388
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_StrongPM2PP3_ModeratePP5_Very_Strong
The NM_000533.5(PLP1):c.453+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
PLP1
NM_000533.5 splice_donor
NM_000533.5 splice_donor
Scores
2
3
Splicing: ADA: 0.9998
2
Clinical Significance
Conservation
PhyloP100: 5.26
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 Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.31294963 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of -42, new splice context is: cggGTgtgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
?
Variant X-103786728-T-C is Pathogenic according to our data. Variant chrX-103786728-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 503691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLP1 | NM_000533.5 | c.453+2T>C | splice_donor_variant | ENST00000621218.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLP1 | ENST00000621218.5 | c.453+2T>C | splice_donor_variant | 1 | NM_000533.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pelizaeus-Merzbacher disease Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 24, 2000 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | - | This intronic variant (c.453+2T>C) is predicted to affect proper splicing of the PLP1 mRNA. It has not been observed in population databases (gnomAD), but functional studies showing a deleterious effect have been reported in the literature (PMID 11071483, PMID 16287154). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2018 | The c.453+2 T>C pathogenic variant in the PLP1 gene has been previously reported in a male with classic Pelizaeus-Merzbacher disease (Hobson et al., 2000). Published functional studies demonstrate that c.453+2 T>C resulted in absent PLP1 protein. (Hobson et al., 2006). This pathogenic variant destroys the canonical splice donor site of intron 3 and is expected to cause abnormal gene splicing. This variant is not observed in large population cohorts (Lek et al.2016). Therefore, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at