rs797045064

Positions:

• chrX-103776996-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000533.5(PLP1):​c.1A>G​(p.Met1?) variant causes a start lost 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLP1 NM_000533.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.76

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 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103776996-A-G is Pathogenic according to our data. Variant chrX-103776996-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 209183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLP1	NM_000533.5	c.1A>G	p.Met1?	start_lost	1/7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.1A>G	p.Met1?	start_lost	1/7	1	NM_000533.5	ENSP00000484450	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 209183). Disruption of the initiator codon has been observed in individuals with clinical features of PLP1-related conditions (PMID: 8786077, 10417279, 12910435, 22343157). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the PLP1 mRNA. The next in-frame methionine is located at codon 206. -

Pelizaeus-Merzbacher disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 23, 2014

This variant has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 23-year-old male with intellectual disability, hearing loss, vision loss, hypertonicity/spasticity, joint contractures, similarly affected brother (not tested), mother with neuropathy -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;T;T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.4	N;.;N;N;N;.;N;.;.
REVEL	Uncertain	0.63
Sift	Benign	0.046	D;.;D;D;T;.;T;.;.
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D
Polyphen		0.0040, 0.0	.;.;.;.;.;B;.;B;B
Vest4		0.91, 0.92, 0.83
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);Gain of catalytic residue at M1 (P = 0.0523);
MVP		1.0
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.41
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs797045064; hg19: chrX-103031924;