X-103786688-TGTC-AGT

Variant names:

• chrX-103786688-TGTC-AGT
• rs1556267287
• NM_000533.5:c.415_418delTGTCinsAGT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_000533.5(PLP1):​c.415_418delTGTCinsAGT​(p.Cys139SerfsTer8) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.72
• 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 13 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 2, Pelizeaus-Merzbacher spectrum disorder, Pelizaeus-Merzbacher disease in female carriers, null syndrome, Pelizaeus-Merzbacher disease, transitional form, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease, connatal form.
• PP5: Variant X-103786688-TGTC-AGT is Pathogenic according to our data. Variant chrX-103786688-TGTC-AGT is described in ClinVar as Pathogenic. ClinVar VariationId is 533383.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	NM_000533.5	MANE Select	c.415_418delTGTCinsAGT	p.Cys139SerfsTer8	frameshift missense	Exon 3 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.415_418delTGTCinsAGT	p.Cys139SerfsTer8	frameshift missense	Exon 4 of 8	NP_001122306.1
	PLP1	NM_001305004.1		c.250_253delTGTCinsAGT	p.Cys84SerfsTer8	frameshift missense	Exon 3 of 7	NP_001291933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.415_418delTGTCinsAGT	p.Cys139SerfsTer8	frameshift missense	Exon 3 of 7	ENSP00000484450.1
	PLP1	ENST00000619236.1	TSL:1	c.348+67_348+70delTGTCinsAGT		intron	N/A	ENSP00000477619.1
	PLP1	ENST00000612423.4	TSL:2	c.415_418delTGTCinsAGT	p.Cys139SerfsTer8	frameshift missense	Exon 4 of 8	ENSP00000481006.1

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 as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary spastic paraplegia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1556267287; hg19: chrX-103041617;