rs2233696

Variant names:

• chrX-103785471-T-C
• rs2233696
• NM_000533.5:c.5-111T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000533.5(PLP1):​c.5-111T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 645,540 control chromosomes in the GnomAD database, including 47,332 homozygotes. There are 88,687 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (9912 hom., 15600 hem., cov: 23)
  • Exomes 𝑓: 0.44 (37420 hom. 73087 hem.)
• Consequence: PLP1 NM_000533.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0150

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-103785471-T-C is Benign according to our data. Variant chrX-103785471-T-C is described in ClinVar as [Benign]. Clinvar id is 670482.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5	c.5-111T>C		intron_variant	Intron 1 of 6	ENST00000621218.5	NP_000524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5	c.5-111T>C		intron_variant	Intron 1 of 6	1	NM_000533.5	ENSP00000484450.1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 54105 AN: 110737 Hom.: 9908 Cov.: 23 AF XY: 0.471 AC XY: 15559 AN XY: 33001

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.494

GnomAD4 exome AF: 0.442 AC: 236257 AN: 534747 Hom.: 37420 AF XY: 0.432 AC XY: 73087 AN XY: 169019

Gnomad4 AFR exome AF: 0.638

Gnomad4 AMR exome AF: 0.518

Gnomad4 ASJ exome AF: 0.503

Gnomad4 EAS exome AF: 0.362

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.416

Gnomad4 NFE exome AF: 0.452

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.489 AC: 54146 AN: 110793 Hom.: 9912 Cov.: 23 AF XY: 0.472 AC XY: 15600 AN XY: 33067

Gnomad4 AFR AF: 0.621

Gnomad4 AMR AF: 0.481

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.378

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.496

Alfa AF: 0.449 Hom.: 10501

Bravo AF: 0.507

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.38

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: rs2233696; hg19: chrX-103040400; COSMIC: COSV58276328; COSMIC: COSV58276328;