rs132630282

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000533.5(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).

Frequency

Genomes: not found (cov: 22)

Consequence

PLP1
NM_000533.5 missense

Scores

7
4
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.54
Variant links:
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 topological_domain Extracellular (size 55) in uniprot entity MYPR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000533.5
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
PLP1NM_000533.5 linkuse as main transcriptc.544A>C p.Thr182Pro missense_variant 4/7 ENST00000621218.5 NP_000524.3 P60201-1A8K9L3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLP1ENST00000621218.5 linkuse as main transcriptc.544A>C p.Thr182Pro missense_variant 4/71 NM_000533.5 ENSP00000484450.1 P60201-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
22
ExAC
AF:
0.0000659
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 providedliterature onlyOMIMOct 01, 1992- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D;D;.
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.74
T;.;T
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.7
L;L;.
PrimateAI
Uncertain
0.57
T
Sift4G
Uncertain
0.011
D;D;D
Polyphen
0.97
D;D;P
Vest4
0.88
MutPred
0.90
Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);.;
MVP
1.0
ClinPred
0.64
D
GERP RS
5.6
Varity_R
0.74
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs132630282; hg19: chrX-103042817; API