rs864622194

Variant names:

• chrX-103776997-T-A
• rs864622194
• NM_000533.5:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chrX-103776997-T-A
• chrX-103776997-T-C
• chrX-103776997-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000533.5(PLP1):​c.2T>A​(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLP1 NM_000533.5 start_lost, splice_region
• Scores: Splicing: ADA: 0.007435
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.55
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-103776997-T-A is Pathogenic according to our data. Variant chrX-103776997-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3255419.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.2T>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 7	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.2T>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 7	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pelizaeus-Merzbacher disease Pathogenic:1

Mar 31, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (c.2T>A, p.Met1Lys) has not been observed in population databases (gnomAD). It has not been described in the literature, although other changes that also alter the initiation codon have been reported (PMID 10417279, 22343157, 8786077, 12910435). Variant prediction programs suggest a deleterious effect on the PLP1 protein, although no functional studies have been published. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.73
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T;T;T;T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
PhyloP100		4.6
PROVEAN	Benign	-1.5	N;.;N;N;N;.;N;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;.;D;D;D;.;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		0.40, 0.044	.;.;.;.;.;B;.;B;B
Vest4		0.92, 0.92, 0.82
MutPred		0.97		Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);Gain of catalytic residue at M1 (P = 0.0121);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		-0.018	Neutral
Varity_R		0.97
gMVP		0.87
Mutation Taster		=5/195	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0074
dbscSNV1_RF	Benign	0.27
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

Other links and lift over

dbSNP: rs864622194; hg19: chrX-103031925;