X-103776998-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_000533.5(PLP1):c.3G>A(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Consequence

PLP1
NM_000533.5 start_lost, splice_region

Scores

Splicing: ADA: 0.08381

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.73

Publications

4 publications found

Variant links:

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]

PLP1 links:

ENSG00000288597 (HGNC:):

ENSG00000288597 links:

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]

RAB9B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-103776998-G-A is Pathogenic according to our data. Variant chrX-103776998-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11087.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLP1	NM_000533.5	MANE Select	c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 7	NP_000524.3
PLP1	NM_001128834.3		c.3G>A	p.Met1?	start_lost splice_region	Exon 2 of 8	NP_001122306.1
PLP1	NM_199478.3		c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 7	NP_955772.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLP1	ENST00000621218.5	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 7	ENSP00000484450.1
PLP1	ENST00000619236.1	TSL:1	c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 7	ENSP00000477619.1
PLP1	ENST00000612423.4	TSL:2	c.3G>A	p.Met1?	start_lost splice_region	Exon 2 of 8	ENSP00000481006.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 2

Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the PLP1 mRNA. The next in-frame methionine is located at codon 206. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with PLP1-related conditions (PMID: 8786077, 10417279, 12910435, 22343157). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11087). For these reasons, this variant has been classified as Pathogenic.

Pelizaeus-Merzbacher disease, mild

Pathogenic:1

Mar 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.72

BayesDel_noAF

Pathogenic

0.70

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.93

PhyloP100

5.7

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.68

Sift

Uncertain

0.027

Sift4G

Uncertain

0.031

Polyphen

0.0

Vest4

0.79

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.017)

MVP

1.0

ClinPred

0.94

GERP RS

5.4

PromoterAI

0.0078

Neutral

(source)

Varity_R

0.62

gMVP

0.69

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.084

dbscSNV1_RF

Benign

0.28

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over