rs132630292

Positions:

• chrX-103786707-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000533.5(PLP1):​c.434G>A​(p.Trp145Ter) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.58

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103786707-G-A is Pathogenic according to our data. Variant chrX-103786707-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11090.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.434G>A	p.Trp145Ter	stop_gained	3/7	ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.434G>A	p.Trp145Ter	stop_gained	3/7	1	NM_000533.5	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 18, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PLP1 are known to be pathogenic (PMID: 18470932). This variant has been observed to be de novo in twin siblings affected with PLP1-related disease (PMID: 7488049). This variant has also been observed to segregate with PLP1-related disease in a family (PMID: 9056547). This variant is also known as p.Trp144* in the literature. ClinVar contains an entry for this variant (Variation ID: 11090). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp145*) in the PLP1 gene. It is expected to result in an absent or disrupted protein product. -

Pelizaeus-Merzbacher disease, atypical Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 17, 1997

- -

Pelizaeus-Merzbacher disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Nov 29, 2021

This nonsense variant (c.434G>A, p.Trp145*) has not been observed in population databases (gnomAD). It has been described in the literature, and found in twin affected males (PMID 7488049, PMID 9056547). No functional studies have been published. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.99
GERP RS		4.9

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: rs132630292; hg19: chrX-103041636; COSMIC: COSV100393224; COSMIC: COSV100393224;