X-103790553-C-G

Variant names:

• chrX-103790553-C-G
• NM_000533.5:c.789C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000533.5(PLP1):​c.789C>G​(p.Tyr263*) 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.79

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.054 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103790553-C-G is Pathogenic according to our data. Variant chrX-103790553-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2575061.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.789C>G	p.Tyr263*	stop_gained	Exon 7 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.789C>G	p.Tyr263*	stop_gained	Exon 7 of 7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pelizaeus-Merzbacher disease;C1839264:Hereditary spastic paraplegia 2 Pathogenic:1

-

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has not yet been detected in the general population (gnomAD). It has also not yet been described in the literature, the dbSNP151 database or the ClinVar database. Another nucleotide exchange at the same position (NM_000533.5:c.789C>A, p.(Tyr263*)) is reported twice in ClinVar as probably pathogenic without indication of a phenotype (variation ID 448087). Another nonsense variant, also located in the last exon of the PLP1 gene and more distal than the variation reported here, is listed in ClinVar as pathogenic in association with an SPG2 (variation ID 488580). In the literature, a cytotoxic effect is discussed as a pathomechanism of point mutations (usually missense variants) in PLP1-associated diseases, resulting in a more severe phenotype than the complete absence of the protein due to nonsense variants3,4. Because the variant detected here affects the last exon of the PLP1 gene, no conclusions about the molecular mechanism underlying the variant are possible at the current level of knowledge. Therefore, the variant has been considered as a "likely pathogenic" (ACMG criteria). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.73
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-103045481;