rs475827

Variant names:

• chrX-103775144-G-A
• rs475827
• ENST00000867705.1:c.-607G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000867704.1(PLP1):​c.-204+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 111,566 control chromosomes in the GnomAD database, including 1,700 homozygotes. There are 6,244 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (1700 hom., 6244 hem., cov: 23)
• Consequence: PLP1 ENST00000867704.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900
• 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]

PLP1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 2

  Inheritance: XL Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics
• Pelizeaus-Merzbacher spectrum disorder

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• null syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• Pelizaeus-Merzbacher disease in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• Pelizaeus-Merzbacher disease, classic form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• Pelizaeus-Merzbacher disease, connatal form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• Pelizaeus-Merzbacher disease, transitional form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288597 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000867704.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000867705.1		c.-607G>A		5_prime_UTR	Exon 1 of 8	ENSP00000537764.1
	PLP1	ENST00000867699.1		c.-144+776G>A		intron	N/A	ENSP00000537758.1
	PLP1	ENST00000867700.1		c.-144+776G>A		intron	N/A	ENSP00000537759.1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 21964 AN: 111511 Hom.: 1700 Cov.: 23

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0408

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.157

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.197 AC: 21980 AN: 111566 Hom.: 1700 Cov.: 23 AF XY: 0.185 AC XY: 6244 AN XY: 33772

African (AFR) AF: 0.160 AC: 4917 AN: 30716

American (AMR) AF: 0.185 AC: 1962 AN: 10577

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 450 AN: 2641

East Asian (EAS) AF: 0.0409 AC: 146 AN: 3571

South Asian (SAS) AF: 0.187 AC: 497 AN: 2654

European-Finnish (FIN) AF: 0.193 AC: 1162 AN: 6026

Middle Eastern (MID) AF: 0.157 AC: 34 AN: 216

European-Non Finnish (NFE) AF: 0.233 AC: 12326 AN: 52974

Other (OTH) AF: 0.180 AC: 273 AN: 1517

Alfa AF: 0.222 Hom.: 23274

Bravo AF: 0.197

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.69
PhyloP100		-0.090
PromoterAI		-0.0072	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs475827; hg19: chrX-103030072;