rs104894707

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_181882.3(PRX):c.2145T>A(p.Cys715Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,593,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PRX
NM_181882.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: -3.48

Variant links:

Genes affected

PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]

PRX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 24 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-40396207-A-T is Pathogenic according to our data. Variant chr19-40396207-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40396207-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRX	NM_181882.3 linkuse as main transcript	c.2145T>A	p.Cys715Ter	stop_gained	7/7	ENST00000324001.8
PRX	NM_001411127.1 linkuse as main transcript	c.2430T>A	p.Cys810Ter	stop_gained	7/7
PRX	XM_017027047.2 linkuse as main transcript	c.2043T>A	p.Cys681Ter	stop_gained	4/4
PRX	NM_020956.2 linkuse as main transcript	c.*2350T>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.2145T>A	p.Cys715Ter	stop_gained	7/7	1	NM_181882.3	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

133170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000112

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251342

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460188

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726462

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000525

AC:

AN:

133282

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

64708

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000112

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000602

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2020	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2022	Nonsense variant predicted to result in protein truncation, as the last 747 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12112076, 21840889, 20625412, 32085570) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -

Charcot-Marie-Tooth disease type 4F

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2002	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 26, 2022	- -

Charcot-Marie-Tooth disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2019

The p.C715* variant (also known as c.2145T>A), located in coding exon 4 of the PRX gene, results from a T to A substitution at nucleotide position 2145. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration has been described homozygous in a brother and sister with Charcot-Marie-Tooth disease type 4F with disease onset prior to age 1 year and slow progression of disease. Additionally, unaffected siblings were either heterozygous or negative for the alteration (Takashima H et al. Ann. Neurol., 2002 Jun;51:709-15; Baets J et al. Brain, 2011 Sep;134:2664-76). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of PRX, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 747 amino acids of the protein, which accounts for over 50% of the protein. Additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. In addition, the truncated region is suggested to be responsible for targeting the protein for ubiquitin-mediated proteolysis (Takashima H et al. Ann. Neurol., 2002 Jun;51:709-15). Studies in mice have also shown protein disruption when this C-terminal region is deleted (Sherman DL et al. Wellcome Open Res, 2018 Mar;3:20). As such, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth disease type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRX protein in which other variant(s) (p.Arg1070*) have been determined to be pathogenic (PMID: 15197604, 15469949, 16770524, 22847150, 26059842). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 4792). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 12112076). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894707, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Cys715*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 747 amino acid(s) of the PRX protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Benign

0.96

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.028

MutationTaster

Benign

1.0

A;A

Vest4

0.68

GERP RS

-8.4

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