rs132630287

Positions:

• chrX-103786691-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000533.5(PLP1):​c.418C>T​(p.His140Tyr) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.08

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 62) in uniprot entity MYPR_HUMAN there are 4 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, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLP1	NM_000533.5	c.418C>T	p.His140Tyr	missense_variant	3/7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.418C>T	p.His140Tyr	missense_variant	3/7	1	NM_000533.5	ENSP00000484450	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1994

- -

Pelizaeus-Merzbacher disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Nov 24, 2021

This missense variant (c.418C>T, p.His140Tyr) has not been observed in population databases (gnomAD). It has been described in the literature (PMID 8012387). There is insufficient evidence available to provide a classification other than uncertain significance for this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.28	A;A;A
PrimateAI	Uncertain	0.74	T
Sift4G	Benign	0.12	T;T
Polyphen		0.015	B;B
Vest4		0.74
MutPred		0.78		Loss of disorder (P = 0.0557);Loss of disorder (P = 0.0557);
MVP		0.96
ClinPred		0.51	D
GERP RS		5.8
Varity_R		0.33
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs132630287; hg19: chrX-103041620;