dbSNP rs132630290: PLP1:p.Met1? (chrX-103776998-G-A) – ACMG Classification: Uncertain_significance (4 pts)

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5 link	c.3G>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5 link	c.3G>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 7	1	NM_000533.5	ENSP00000484450.1

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 v4.3

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

T;T;T;T;T;T;T;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;.;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

PhyloP100

5.7

PROVEAN

Benign

-1.6

N;.;N;N;N;.;N;.;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.027

D;.;D;D;D;.;D;.;.

Sift4G

Uncertain

0.031

D;D;D;D;D;D;D;D;D

Polyphen

0.0

.;.;.;.;.;B;.;B;B

Vest4

0.79, 0.80, 0.76

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.017);Gain of catalytic residue at M1 (P = 0.017);Gain of catalytic residue at M1 (P = 0.017);Gain of catalytic residue at M1 (P = 0.017);Gain of catalytic residue at M1 (P = 0.017);Gain of catalytic residue at M1 (P = 0.017);Gain of catalytic residue at M1 (P = 0.017);Gain of catalytic residue at M1 (P = 0.017);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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over