X-103786726-G-T

Variant names:

• chrX-103786726-G-T
• rs886044450
• NM_000533.5:c.453G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000533.5(PLP1):​c.453G>T​(p.Lys151Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005088468: Functional studies indicate a deleterious effect on protein expression (PMID 12601703, PMID 16287154, PMID 30195779).". Synonymous variant affecting the same amino acid position (i.e. K151K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.58
• Publications: 2 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005088468: Functional studies indicate a deleterious effect on protein expression (PMID 12601703, PMID 16287154, PMID 30195779).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000533.5
• PM2: Very rare variant in population databases, with high coverage
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant X-103786726-G-T is Pathogenic according to our data. Variant chrX-103786726-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3255430.Status of the report is criteria_provided_single_submitter, 1 stars.

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.453G>T	p.Lys151Asn	missense splice_region	Exon 3 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.453G>T	p.Lys151Asn	missense splice_region	Exon 4 of 8	NP_001122306.1	A8K9L3
	PLP1	NM_001305004.1		c.288G>T	p.Lys96Asn	missense splice_region	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.453G>T	p.Lys151Asn	missense splice_region	Exon 3 of 7	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.348+105G>T		intron	N/A	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.495G>T	p.Lys165Asn	missense splice_region	Exon 4 of 8	ENSP00000537771.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Pelizaeus-Merzbacher disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.6
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.97	D
Vest4		0.64
MutPred		0.28		Loss of methylation at K151 (P = 0.0011)
MVP		0.94
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.86
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.18		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: rs886044450; hg19: chrX-103041655; COSMIC: COSV58276238; COSMIC: COSV58276238;