NM_000533.5:c.696+8G>T

Variant names:

• chrX-103788518-G-T
• rs902326390
• NM_000533.5:c.696+8G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000533.5(PLP1):​c.696+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,146,397 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 5 hem.)
• Consequence: PLP1 NM_000533.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001071
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.149
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-103788518-G-T is Benign according to our data. Variant chrX-103788518-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436344.
• BS2: High Hemizygotes in GnomAdExome4 at 5 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.696+8G>T		splice_region intron	N/A	NP_000524.3
	PLP1	NM_001128834.3		c.696+8G>T		splice_region intron	N/A	NP_001122306.1	A8K9L3
	PLP1	NM_199478.3		c.591+8G>T		splice_region 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.696+8G>T		splice_region intron	N/A	ENSP00000484450.1	P60201-1
	PLP1	ENST00000619236.1	TSL:1	c.591+8G>T		splice_region intron	N/A	ENSP00000477619.1	P60201-2
	PLP1	ENST00000867712.1		c.738+8G>T		splice_region intron	N/A	ENSP00000537771.1

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111548 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000242 AC: 25 AN: 1034849 Hom.: 0 Cov.: 25 AF XY: 0.0000162 AC XY: 5 AN XY: 307829

African (AFR) AF: 0.000158 AC: 4 AN: 25241

American (AMR) AF: 0.0000285 AC: 1 AN: 35141

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18992

East Asian (EAS) AF: 0.00 AC: 0 AN: 30007

South Asian (SAS) AF: 0.00 AC: 0 AN: 52675

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.000251 AC: 1 AN: 3980

European-Non Finnish (NFE) AF: 0.0000179 AC: 14 AN: 784251

Other (OTH) AF: 0.000114 AC: 5 AN: 44050

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111548 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33768

African (AFR) AF: 0.0000326 AC: 1 AN: 30680

American (AMR) AF: 0.00 AC: 0 AN: 10495

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2635

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53094

Other (OTH) AF: 0.00 AC: 0 AN: 1493

Alfa AF: 0.000169 Hom.: 1

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	-	not specified (2)
-	-	1	Hereditary spastic paraplegia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.61
PhyloP100		-0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0040
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: rs902326390; hg19: chrX-103043447;