rs878853076

Variant names:

• chrX-103786661-C-A
• rs878853076
• NM_000533.5:c.388C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-103786661-C-A
• chrX-103786661-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_000533.5(PLP1):​c.388C>A​(p.His130Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H130Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000533.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-103786661-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 235599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 2, Pelizeaus-Merzbacher spectrum disorder, Pelizaeus-Merzbacher disease in female carriers, null syndrome, Pelizaeus-Merzbacher disease, transitional form, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease, connatal form.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4172079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.388C>A	p.His130Asn	missense_variant	Exon 3 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.388C>A	p.His130Asn	missense_variant	Exon 3 of 7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 2 Uncertain:1

Aug 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 130 of the PLP1 protein (p.His130Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental disorders and/or hereditary spastic paraplegia (PMID: 33504798; Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant disrupts the p.His130 amino acid residue in PLP1. Other variant(s) that disrupt this residue have been observed in individuals with PLP1-related conditions (PMID: 11093273, 34782662), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.0099	T;T;D;D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	.;T;T;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.0	.;.;N;N
PhyloP100		5.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.41	.;N;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.023	.;D;.;.
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.50
MutPred		0.39		Loss of disorder (P = 0.1035);Loss of disorder (P = 0.1035);Loss of disorder (P = 0.1035);Loss of disorder (P = 0.1035);
MVP		0.96
ClinPred		0.61	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.71
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs878853076; hg19: chrX-103041590;