rs132630282

Positions:

• chrX-103787888-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000621218.5(PLP1):​c.544A>C​(p.Thr182Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T182T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 ENST00000621218.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.54

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]

RAB9B (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000621218.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-103787888-A-C is Pathogenic according to our data. Variant chrX-103787888-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 11079.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-103787888-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLP1	NM_000533.5	c.544A>C	p.Thr182Pro	missense_variant	4/7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.544A>C	p.Thr182Pro	missense_variant	4/7	1	NM_000533.5	ENSP00000484450	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pelizaeus-Merzbacher disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	0.49	A;A;A
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.97	D;D;P
Vest4		0.88
MutPred		0.90		Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);.;
MVP		1.0
ClinPred		0.64	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs132630282; hg19: chrX-103042817;