rs132630291
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000533.5(PLP1):āc.710T>Cā(p.Phe237Ser) variant causes a missense change. 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 Likely pathogenic (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F237V) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 23)
Exomes š: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
PLP1
NM_000533.5 missense
NM_000533.5 missense
Scores
8
5
1
Clinical Significance
Conservation
PhyloP100: 4.75
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 12 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000533.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-103789345-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 816628.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant X-103789346-T-C is Pathogenic according to our data. Variant chrX-103789346-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11089.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLP1 | NM_000533.5 | c.710T>C | p.Phe237Ser | missense_variant | 6/7 | ENST00000621218.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLP1 | ENST00000621218.5 | c.710T>C | p.Phe237Ser | missense_variant | 6/7 | 1 | NM_000533.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1093933Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 359491
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1093933
Hom.:
Cov.:
27
AF XY:
AC XY:
0
AN XY:
359491
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
Pelizaeus-Merzbacher disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jan 25, 2022 | This missense variant (c.710T>C, p.Phe237Ser) has not been observed in population databases (gnomAD). It has been described in the literature in a 5 generation family with numerous affected males (PMID 8956049). Variant prediction programs support a deleterious effect on the protein, although no functional studies have been published. - |
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
Uncertain
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;D
Polyphen
P;P;P
Vest4
MutPred
Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);.;
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