chrX-103776965-C-T

Position:

• chrX-103776965-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000533.5(PLP1):​c.-31C>T variant causes a 5 prime UTR 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 0.394

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]

RAB9B (HGNC:):

ACMG classification

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/exons	MANE	UniProt
PLP1	NM_000533.5	c.-31C>T		5_prime_UTR_variant	1/7	ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.-31C>T		5_prime_UTR_variant	1/7	1	NM_000533.5	P1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 204 AN: 111767 Hom.: 1 Cov.: 23 AF XY: 0.00177 AC XY: 60 AN XY: 33973

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.: 3 AF XY: 0.00243 AC XY: 159 AN XY: 65353

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.: 8 Cov.: 27 AF XY: 0.00136 AC XY: 481 AN XY: 352643

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.: 2 Cov.: 23 AF XY: 0.00182 AC XY: 62 AN XY: 34033

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.: 50

Bravo AF: 0.00238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2021	See Variant Classification Assertion Criteria. -

Pelizaeus-Merzbacher disease, mild Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

Hereditary spastic paraplegia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 23, 2023

- -

Pelizaeus-Merzbacher disease;C1839264:Hereditary spastic paraplegia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Pelizaeus-Merzbacher disease Benign:1

Benign, criteria provided, single submitter

research

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

-

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	14
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

Other links and lift over

dbSNP: rs2233695; hg19: chrX-103031893;