chrX-103786626-CAG-C

Variant names:

• chrX-103786626-CAG-C
• rs1556267123
• NM_000533.5:c.354_355delAG

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000533.5(PLP1):​c.354_355delAG​(p.Gly120ProfsTer83) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000740755: Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ PLP1 alterations affecting exon 3B cause the mildest form of PMD (form 4). Exon 3B is spliced out during messenger RNA production of DM20 and therefore the expression and function of that isoform protein are preserved. The mutant PLP1 protein is much shorter than the wild type and is expected to be degraded via nonsense-mediated decay. The combination of preserved DM20 and lack of mutant PLP1 proteins is what is predicted to result in the mild phenotype ()Osaka, 2010).". Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.29
• Publications: 2 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000740755: Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ PLP1 alterations affecting exon 3B cause the mildest form of PMD (form 4). Exon 3B is spliced out during messenger RNA production of DM20 and therefore the expression and function of that isoform protein are preserved. The mutant PLP1 protein is much shorter than the wild type and is expected to be degraded via nonsense-mediated decay. The combination of preserved DM20 and lack of mutant PLP1 proteins is what is predicted to result in the mild phenotype ()Osaka, 2010).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103786626-CAG-C is Pathogenic according to our data. Variant chrX-103786626-CAG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520586.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.354_355delAG	p.Gly120ProfsTer83	frameshift	Exon 3 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.354_355delAG	p.Gly120ProfsTer83	frameshift	Exon 4 of 8	NP_001122306.1	A8K9L3
	PLP1	NM_001305004.1		c.189_190delAG	p.Gly65ProfsTer83	frameshift	Exon 3 of 7	NP_001291933.1	B4DI30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.354_355delAG	p.Gly120ProfsTer83	frameshift	Exon 3 of 7	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.348+6_348+7delAG		splice_region intron	N/A	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.396_397delAG	p.Gly134ProfsTer83	frameshift	Exon 4 of 8	ENSP00000537771.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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	-	-	Hereditary spastic paraplegia 2 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1556267123; hg19: chrX-103041555;