chrX-103776965-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000533.5(PLP1):c.-31C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,197,630 control chromosomes in the GnomAD database, including 10 homozygotes. There are 543 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., 62 hem., cov: 23)

Exomes 𝑓: 0.0014 ( 8 hom. 481 hem. )

Consequence

PLP1
NM_000533.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 0.394

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant X-103776965-C-T is Benign according to our data. Variant chrX-103776965-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-103776965-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0019 (213/111817) while in subpopulation EAS AF= 0.0224 (79/3531). AF 95% confidence interval is 0.0184. There are 2 homozygotes in gnomad4. There are 62 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.-31C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000621218.5	NP_000524.3	P60201-1A8K9L3
PLP1	NM_000533.5 link	c.-31C>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000621218.5	NP_000524.3	P60201-1A8K9L3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLP1	ENST00000621218 link	c.-31C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_000533.5	ENSP00000484450.1		P60201-1
PLP1	ENST00000621218 link	c.-31C>T		5_prime_UTR_variant	Exon 1 of 7	1	NM_000533.5	ENSP00000484450.1		P60201-1

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

204

AN:

111767

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

AN XY:

33973

show subpopulations

Gnomad AFR

AF:

0.000228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00737

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0223

Gnomad SAS

AF:

0.00188

Gnomad FIN

AF:

0.000989

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000414

Gnomad OTH

AF:

0.00463

GnomAD3 exomes

AF:

0.00343

AC:

619

AN:

180671

Hom.:

AF XY:

0.00243

AC XY:

159

AN XY:

65353

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0180

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.000818

Gnomad NFE exome

AF:

0.000224

Gnomad OTH exome

AF:

0.00178

GnomAD4 exome

AF:

0.00144

AC:

1566

AN:

1085813

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

481

AN XY:

352643

show subpopulations

Gnomad4 AFR exome

AF:

0.000153

Gnomad4 AMR exome

AF:

0.0121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0226

Gnomad4 SAS exome

AF:

0.00123

Gnomad4 FIN exome

AF:

0.00168

Gnomad4 NFE exome

AF:

0.000283

Gnomad4 OTH exome

AF:

0.00195

GnomAD4 genome

AF:

0.00190

AC:

213

AN:

111817

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

AN XY:

34033

show subpopulations

Gnomad4 AFR

AF:

0.000227

Gnomad4 AMR

AF:

0.00727

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0224

Gnomad4 SAS

AF:

0.00188

Gnomad4 FIN

AF:

0.000989

Gnomad4 NFE

AF:

0.000414

Gnomad4 OTH

AF:

0.0111

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.00238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 18, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 13, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Sep 19, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pelizaeus-Merzbacher disease, mild

Uncertain:1

Jan 01, 1996

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary spastic paraplegia 2

Benign:1

Mar 23, 2023

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

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pelizaeus-Merzbacher disease

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The hemizygous c.-31C>T variant in PLP1 has been identified in a Japanese individual with Perlizaeus-Merzbacher disease (PMID: 8723686), and has been identified in >2% of East Asian chromosomes, 61 hemizygotes, and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for X-linked recessive Perlizaeus-Merzbacher disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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