rs2233697

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_001305004.1(PLP1):c.5-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,207,098 control chromosomes in the GnomAD database, including 10 homozygotes. There are 551 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., 59 hem., cov: 23)

Exomes 𝑓: 0.0014 ( 8 hom. 492 hem. )

Consequence

PLP1
NM_001305004.1 splice_acceptor, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.15

Variant links:

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 links:

ENSG00000288597 (HGNC:):

ENSG00000288597 links:

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]

RAB9B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.1, offset of -1, new splice context is: atttctccaaaaactaccAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant X-103785745-A-G is Benign according to our data. Variant chrX-103785745-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-103785745-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00184 (206/111795) while in subpopulation EAS AF= 0.0207 (73/3520). AF 95% confidence interval is 0.0169. There are 2 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5 link	c.168A>G	p.Gln56Gln	synonymous_variant	Exon 2 of 7	ENST00000621218.5	NP_000524.3	P60201-1A8K9L3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218.5 link	c.168A>G	p.Gln56Gln	synonymous_variant	Exon 2 of 7	1	NM_000533.5	ENSP00000484450.1		P60201-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

197

AN:

111741

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

AN XY:

33943

show subpopulations

Gnomad AFR

AF:

0.000228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00755

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0207

Gnomad SAS

AF:

0.00189

Gnomad FIN

AF:

0.000815

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000414

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00347

AC:

636

AN:

183425

Hom.:

AF XY:

0.00261

AC XY:

177

AN XY:

67881

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0184

Gnomad SAS exome

AF:

0.000996

Gnomad FIN exome

AF:

0.000812

Gnomad NFE exome

AF:

0.000244

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00143

AC:

1569

AN:

1095303

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

492

AN XY:

360697

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0226

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.00168

Gnomad4 NFE exome

AF:

0.000275

Gnomad4 OTH exome

AF:

0.00196

GnomAD4 genome

AF:

0.00184

AC:

206

AN:

111795

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

AN XY:

34007

show subpopulations

Gnomad4 AFR

AF:

0.000228

Gnomad4 AMR

AF:

0.00745

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0207

Gnomad4 SAS

AF:

0.00189

Gnomad4 FIN

AF:

0.000815

Gnomad4 NFE

AF:

0.000414

Gnomad4 OTH

AF:

0.00988

Alfa

AF:

0.00182

Hom.:

Bravo

AF:

0.00235

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 07, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 2

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pelizaeus-Merzbacher disease;C1839264:Hereditary spastic paraplegia 2

Benign:1

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 25, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PLP1-related disorder

Benign:1

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.7

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over