rs1556267388

Positions:

• chrX-103786728-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Strong PM2 PP3_Moderate PP5_Very_Strong

The NM_000533.5(PLP1):​c.453+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 splice_donor
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.26

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.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.31294963 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of -42, new splice context is: cggGTgtgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant X-103786728-T-C is Pathogenic according to our data. Variant chrX-103786728-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 503691.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.453+2T>C		splice_donor_variant		ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.453+2T>C		splice_donor_variant		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

Pelizaeus-Merzbacher disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 24, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	-	This intronic variant (c.453+2T>C) is predicted to affect proper splicing of the PLP1 mRNA. It has not been observed in population databases (gnomAD), but functional studies showing a deleterious effect have been reported in the literature (PMID 11071483, PMID 16287154). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2018

The c.453+2 T>C pathogenic variant in the PLP1 gene has been previously reported in a male with classic Pelizaeus-Merzbacher disease (Hobson et al., 2000). Published functional studies demonstrate that c.453+2 T>C resulted in absent PLP1 protein. (Hobson et al., 2006). This pathogenic variant destroys the canonical splice donor site of intron 3 and is expected to cause abnormal gene splicing. This variant is not observed in large population cohorts (Lek et al.2016). Therefore, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	33
DANN	Benign	0.92
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.18		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: rs1556267388; hg19: chrX-103041657;