rs132630279

Positions:

• chrX-103787831-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000533.5(PLP1):​c.487T>C​(p.Trp163Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a transmembrane_region Helical; Name=3 (size 25) in uniprot entity MYPR_HUMAN there are 8 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, 0.993
• PP5: Variant X-103787831-T-C is Pathogenic according to our data. Variant chrX-103787831-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLP1	NM_000533.5	c.487T>C	p.Trp163Arg	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.487T>C	p.Trp163Arg	missense_variant	4/7	1	NM_000533.5	ENSP00000484450	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PLP1: PM2, PM5, PS4:Moderate, PP2, PP3 -

Pelizaeus-Merzbacher disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1989	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Dec 15, 2021	This missense variant (c.487T>C, p.Trp163Arg) has not been observed in population databases (gnomAD). It has been described in the literature (PMID 2479017, PMID 3827224, PMID 8696336), and functional studies have shown a deleterious effect on protein expression. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.94
MutPred		0.95		Gain of methylation at W163 (P = 0.0155);Gain of methylation at W163 (P = 0.0155);.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.97
gMVP		1.0

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

Other links and lift over

dbSNP: rs132630279; hg19: chrX-103042760;