X-103786728-T-C

Variant names:

• chrX-103786728-T-C
• rs1556267388
• NM_000533.5:c.453+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_000533.5(PLP1):​c.453+2T>C variant causes a splice donor, intron 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 (★★). ClinVar reports functional evidence for this variant: "SCV005077960: Functional studies showing a deleterious effect have been reported in the literature (PMID 11071483, PMID 16287154)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.26
• Publications: 0 publications found

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]

ENSG00000288597 (HGNC:):

RAB9B (HGNC:14090): (RAB9B, member RAS oncogene family) This gene encodes a member of a subfamily of RAS small guanosine triphosphate (GTP)-binding proteins that regulate membrane trafficking. The encoded protein may be involved in endosome-to-Golgi transport. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.3141487 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005077960: Functional studies showing a deleterious effect have been reported in the literature (PMID 11071483, PMID 16287154).; SCV000709927: Published functional studies demonstrate that c.453+2 T>C resulted in absent PLP1 protein. (Hobson et al., 2006).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103786728-T-C is Pathogenic according to our data. Variant chrX-103786728-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 503691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000533.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	NM_000533.5	MANE Select	c.453+2T>C		splice_donor intron	N/A	NP_000524.3
	PLP1	NM_001128834.3		c.453+2T>C		splice_donor intron	N/A	NP_001122306.1	A8K9L3
	PLP1	NM_199478.3		c.348+107T>C		intron	N/A	NP_955772.1	P60201-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.453+2T>C		splice_donor intron	N/A	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.348+107T>C		intron	N/A	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.495+2T>C		splice_donor intron	N/A	ENSP00000537771.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Pelizaeus-Merzbacher disease (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.3
GERP RS		4.6
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1556267388; hg19: chrX-103041657;