X-103786682-C-T

Variant names:

• chrX-103786682-C-T
• rs132630295
• NM_000533.5:c.409C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137G) has been classified as Likely pathogenic.

• 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:2
• Conservation: PhyloP100: 2.42
• Publications: 19 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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-103786682-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2230585.
• 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 Pelizeaus-Merzbacher spectrum disorder, null syndrome, hereditary spastic paraplegia 2, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease in female carriers, Pelizaeus-Merzbacher disease, connatal form, Pelizaeus-Merzbacher disease, transitional form.
• 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 VariationId is 11098.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000533.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	NM_000533.5	MANE Select	c.409C>T	p.Arg137Trp	missense	Exon 3 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.409C>T	p.Arg137Trp	missense	Exon 4 of 8	NP_001122306.1	A8K9L3
	PLP1	NM_001305004.1		c.244C>T	p.Arg82Trp	missense	Exon 3 of 7	NP_001291933.1	B4DI30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.409C>T	p.Arg137Trp	missense	Exon 3 of 7	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.348+61C>T		intron	N/A	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.451C>T	p.Arg151Trp	missense	Exon 4 of 8	ENSP00000537771.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841378

Other (OTH) AF: 0.00 AC: 0 AN: 46071

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

Alfa AF: 0.000131 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Hereditary spastic paraplegia 2 (2)
-	1	-	not specified (1)
1	-	-	Pelizaeus-Merzbacher disease (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.66		Loss of disorder (P = 0.0182)
MVP		1.0
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.93
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs132630295; hg19: chrX-103041611; COSMIC: COSV58277298; COSMIC: COSV58277298;