rs2233697

chrX-103785745-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000533.5(PLP1):c.168A>G(p.Gln56=) variant causes a synonymous 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. 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_000533.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• 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].
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• 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. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLP1	NM_000533.5	c.168A>G	p.Gln56=	synonymous_variant	2/7	ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.168A>G	p.Gln56=	synonymous_variant	2/7	1	NM_000533.5	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 197 AN: 111741 Hom.: 1 Cov.: 23 AF XY: 0.00168 AC XY: 57 AN XY: 33943

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.: 3 AF XY: 0.00261 AC XY: 177 AN XY: 67881

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.: 8 Cov.: 29 AF XY: 0.00136 AC XY: 492 AN XY: 360697

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.: 2 Cov.: 23 AF XY: 0.00173 AC XY: 59 AN XY: 34007

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.: 15

Bravo AF: 0.00235

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 07, 2013

- -

Hereditary spastic paraplegia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2014

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 20, 2017

- -

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

Other links and lift over

dbSNP: rs2233697; hg19: chrX-103040674; COSMIC: COSV58275905; COSMIC: COSV58275905;