rs1126707

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000533.5(PLP1):c.609T>C(p.Asp203Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,206,198 control chromosomes in the GnomAD database, including 35,090 homozygotes. There are 111,962 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 2706 hom., 7800 hem., cov: 23)

Exomes 𝑓: 0.29 ( 32384 hom. 104162 hem. )

Consequence

PLP1
NM_000533.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.61

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant X-103787953-T-C is Benign according to our data. Variant chrX-103787953-T-C is described in ClinVar as [Benign]. Clinvar id is 93232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-103787953-T-C is described in Lovd as [Benign]. Variant chrX-103787953-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLP1	NM_000533.5 link	c.609T>C	p.Asp203Asp	synonymous_variant	Exon 4 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.609T>C	p.Asp203Asp	synonymous_variant	Exon 4 of 7	1	NM_000533.5	ENSP00000484450.1		P60201-1

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

27110

AN:

111427

Hom.:

2708

Cov.:

AF XY:

0.232

AC XY:

7793

AN XY:

33623

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.371

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.298

Gnomad OTH

AF:

0.273

GnomAD3 exomes

AF:

0.285

AC:

52242

AN:

183021

Hom.:

5263

AF XY:

0.280

AC XY:

18879

AN XY:

67543

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.408

Gnomad ASJ exome

AF:

0.359

Gnomad EAS exome

AF:

0.245

Gnomad SAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.300

Gnomad OTH exome

AF:

0.285

GnomAD4 exome

AF:

0.291

AC:

319080

AN:

1094715

Hom.:

32384

Cov.:

AF XY:

0.289

AC XY:

104162

AN XY:

360679

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.400

Gnomad4 ASJ exome

AF:

0.354

Gnomad4 EAS exome

AF:

0.269

Gnomad4 SAS exome

AF:

0.199

Gnomad4 FIN exome

AF:

0.258

Gnomad4 NFE exome

AF:

0.300

Gnomad4 OTH exome

AF:

0.283

GnomAD4 genome

AF:

0.243

AC:

27104

AN:

111483

Hom.:

2706

Cov.:

AF XY:

0.232

AC XY:

7800

AN XY:

33689

show subpopulations

Gnomad4 AFR

AF:

0.116

Gnomad4 AMR

AF:

0.328

Gnomad4 ASJ

AF:

0.371

Gnomad4 EAS

AF:

0.253

Gnomad4 SAS

AF:

0.170

Gnomad4 FIN

AF:

0.230

Gnomad4 NFE

AF:

0.298

Gnomad4 OTH

AF:

0.268

Alfa

AF:

0.296

Hom.:

7713

Bravo

AF:

0.249

EpiCase

AF:

0.296

EpiControl

AF:

0.294

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Nov 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

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. -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 2

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Jul 24, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases

Benign:1

Nov 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pelizaeus-Merzbacher disease

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.60

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

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