chrX-103776998-G-A

Position:

• chrX-103776998-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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

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]

RAB9B (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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 id is 11087.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLP1	NM_000533.5	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/7	ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/7	1	NM_000533.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.70
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;T;T;T;T;T;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	A;A;A
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	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs132630290; hg19: chrX-103031926;