NM_000533.5:c.5-16C>A

Variant names:

• chrX-103785566-C-A
• NM_000533.5:c.5-16C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000533.5(PLP1):​c.5-16C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,089,195 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 2 hem.)
• Consequence: PLP1 NM_000533.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.47
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant X-103785566-C-A is Benign according to our data. Variant chrX-103785566-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3709185.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.5-16C>A		intron	N/A	NP_000524.3
	PLP1	NM_001128834.3		c.5-16C>A		intron	N/A	NP_001122306.1	A8K9L3
	PLP1	NM_199478.3		c.5-16C>A		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.5-16C>A		intron	N/A	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.5-16C>A		intron	N/A	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.5-16C>A		intron	N/A	ENSP00000537771.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000138 AC: 15 AN: 1089195 Hom.: 0 Cov.: 29 AF XY: 0.00000563 AC XY: 2 AN XY: 355513

African (AFR) AF: 0.00 AC: 0 AN: 26214

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 53917

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3731

European-Non Finnish (NFE) AF: 0.0000180 AC: 15 AN: 834327

Other (OTH) AF: 0.00 AC: 0 AN: 45790

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.3
DANN	Benign	0.71
PhyloP100		-1.5

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

hg19: chrX-103040495;