rs1060500908

Variant names:

• chrX-103789337-A-T
• rs1060500908
• NM_000533.5:c.701A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000533.5(PLP1):​c.701A>T​(p.Gln234Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69
• Publications: 0 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 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 hereditary spastic paraplegia 2, Pelizeaus-Merzbacher spectrum disorder, Pelizaeus-Merzbacher disease in female carriers, null syndrome, Pelizaeus-Merzbacher disease, transitional form, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease, connatal form.

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.701A>T	p.Gln234Leu	missense	Exon 6 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.701A>T	p.Gln234Leu	missense	Exon 7 of 8	NP_001122306.1
	PLP1	NM_199478.3		c.596A>T	p.Gln199Leu	missense	Exon 6 of 7	NP_955772.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.701A>T	p.Gln234Leu	missense	Exon 6 of 7	ENSP00000484450.1
	PLP1	ENST00000619236.1	TSL:1	c.596A>T	p.Gln199Leu	missense	Exon 6 of 7	ENSP00000477619.1
	PLP1	ENST00000867712.1		c.743A>T	p.Gln248Leu	missense	Exon 7 of 8	ENSP00000537771.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.55	T
Polyphen		0.41	B
Vest4		0.42
MutPred		0.72		Loss of catalytic residue at Q234 (P = 0.001)
MVP		0.98
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.30
gMVP		0.94
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060500908; hg19: chrX-103044266;