chrX-103786682-C-T

Position:

• chrX-103786682-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000533.5(PLP1):​c.409C>T​(p.Arg137Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,417 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.42

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

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Myelin proteolipid protein (size 275) in uniprot entity MYPR_HUMAN there are 52 pathogenic changes around while only 0 benign (100%) in NM_000533.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant X-103786682-C-T is Pathogenic according to our data. Variant chrX-103786682-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11098.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLP1	NM_000533.5	c.409C>T	p.Arg137Trp	missense_variant	3/7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.409C>T	p.Arg137Trp	missense_variant	3/7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097417 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362785

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 2 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2018	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. The observation of one or more missense substitutions at this codon (p,Arg137Gly) in affected individuals suggests that this may be a clinically significant residue (PMID: 24139698). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with complicated spastic paraplegia and in an individual affected with Pelizaeus-Merzbacher disease (PMID: 17438221, 24139698). ClinVar contains an entry for this variant (Variation ID: 11098). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 137 of the PLP1 protein (p.Arg137Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 17, 2007	- -

Pelizaeus-Merzbacher disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Nov 22, 2021

This missense variant (c.409G>T, p.Arg137Trp) has not been observed in population databases (gnomAD). It has been described in the literature (PMID 17438221, PMID 24139698). This nucleotide resides in a region involved in splice site regulation (PMID 16288477), and variant prediction programs suggest a deleterious effect on the PLP1 protein, although no functional studies have been published. It has been found in 2 affected males in a family, related through maternal lines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;L
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.54
MutPred		0.66		Loss of disorder (P = 0.0182);Loss of disorder (P = 0.0182);
MVP		1.0
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs132630295; hg19: chrX-103041611; COSMIC: COSV58277298; COSMIC: COSV58277298;