rs1556268920

Variant names:

• chrX-103787829-T-C
• rs1556268920
• NM_000533.5:c.485T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000533.5(PLP1):​c.485T>C​(p.Val162Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V162V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40967083).

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.485T>C	p.Val162Ala	missense	Exon 4 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.485T>C	p.Val162Ala	missense	Exon 5 of 8	NP_001122306.1	A8K9L3
	PLP1	NM_199478.3		c.380T>C	p.Val127Ala	missense	Exon 4 of 7	NP_955772.1	P60201-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.485T>C	p.Val162Ala	missense	Exon 4 of 7	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.380T>C	p.Val127Ala	missense	Exon 4 of 7	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.527T>C	p.Val176Ala	missense	Exon 5 of 8	ENSP00000537771.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

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	Benign	0.20
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.59
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	-0.69	N
PhyloP100		4.7
PrimateAI	Uncertain	0.57	T
Sift4G	Benign	0.12	T
Polyphen		0.081	B
Vest4		0.14
MutPred		0.53		Loss of stability (P = 0.1576)
MVP		0.64
ClinPred		0.30	T
GERP RS		5.7
Varity_R		0.12
gMVP		0.87
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs1556268920; hg19: chrX-103042758;