chrX-103776965-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

3 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 220658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

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
PLP1	NM_000533.5 link	c.-31C>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000621218.5	NP_000524.3

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

204

AN:

111767

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00343

AC:

619

AN:

180671

AF XY:

0.00243

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 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

African (AFR)

AF:

0.000153

AC:

AN:

26177

American (AMR)

AF:

0.0121

AC:

424

AN:

35132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19297

East Asian (EAS)

AF:

0.0226

AC:

680

AN:

30090

South Asian (SAS)

AF:

0.00123

AC:

AN:

53583

European-Finnish (FIN)

AF:

0.00168

AC:

AN:

40493

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.000283

AC:

235

AN:

831257

Other (OTH)

AF:

0.00195

AC:

AN:

45694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00190

AC:

213

AN:

111817

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

AN XY:

34033

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30816

American (AMR)

AF:

0.00727

AC:

AN:

10591

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.0224

AC:

AN:

3531

South Asian (SAS)

AF:

0.00188

AC:

AN:

2654

European-Finnish (FIN)

AF:

0.000989

AC:

AN:

6067

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000414

AC:

AN:

53082

Other (OTH)

AF:

0.0111

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00148

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 19, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

(source)

DANN

Benign

0.87

PhyloP100

0.39

PromoterAI

-0.22

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over