X-103786726-G-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• 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

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 Pathogenic. Variant got 10 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: Splicing scoreres supports a deletorius 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 id is 3255430.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.453G>T	p.Lys151Asn	missense_variant, splice_region_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.453G>T	p.Lys151Asn	missense_variant, splice_region_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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pelizaeus-Merzbacher disease Pathogenic:1

Dec 10, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (c.453G>T, p.Lys151Asn) is the last nucleotide af exon 3. It has not been observed in population databases (gnomAD). It has been described in the literature, and functional studies indicate a deleterious effect on protein expression (PMID 12601703, PMID 16287154, PMID 30195779). -

Computational scores

Source: dbNSFP v4.3

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;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.97	D;D
Vest4		0.64
MutPred		0.28		Loss of methylation at K151 (P = 0.0011);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-103041655; COSMIC: COSV58276238; COSMIC: COSV58276238;