NM_000533.5:c.5-111T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 VariationId 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.

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.5-111T>C		intron	N/A	NP_000524.3
	PLP1	NM_001128834.3		c.5-111T>C		intron	N/A	NP_001122306.1	A8K9L3
	PLP1	NM_199478.3		c.5-111T>C		intron	N/A	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.5-111T>C		intron	N/A	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.5-111T>C		intron	N/A	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.5-111T>C		intron	N/A	ENSP00000537771.1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 54105 AN: 110737 Hom.: 9908 Cov.: 23

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

African (AFR) AF: 0.638 AC: 9654 AN: 15138

American (AMR) AF: 0.518 AC: 16120 AN: 31108

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 7280 AN: 14475

East Asian (EAS) AF: 0.362 AC: 9893 AN: 27365

South Asian (SAS) AF: 0.264 AC: 10326 AN: 39106

European-Finnish (FIN) AF: 0.416 AC: 15026 AN: 36162

Middle Eastern (MID) AF: 0.450 AC: 824 AN: 1831

European-Non Finnish (NFE) AF: 0.452 AC: 154575 AN: 342343

Other (OTH) AF: 0.461 AC: 12559 AN: 27219

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

African (AFR) AF: 0.621 AC: 18883 AN: 30402

American (AMR) AF: 0.481 AC: 5053 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1401 AN: 2636

East Asian (EAS) AF: 0.378 AC: 1313 AN: 3477

South Asian (SAS) AF: 0.226 AC: 600 AN: 2650

European-Finnish (FIN) AF: 0.394 AC: 2327 AN: 5899

Middle Eastern (MID) AF: 0.479 AC: 104 AN: 217

European-Non Finnish (NFE) AF: 0.445 AC: 23507 AN: 52835

Other (OTH) AF: 0.496 AC: 747 AN: 1506

Alfa AF: 0.463 Hom.: 16446

Bravo AF: 0.507

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.38
PhyloP100		0.015
Mutation Taster		=100/0	polymorphism (auto)

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