rs104894714

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_181882.3(PRX):c.2857C>T(p.Arg953*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R953R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PRX
NM_181882.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.653

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 4
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 4F
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
Charcot-Marie-Tooth disease type 3
Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

PRX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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 26 pathogenic variants in the truncated region.

PP5

Variant 19-40395495-G-A is Pathogenic according to our data. Variant chr19-40395495-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PRX	NM_181882.3 link	c.2857C>T	p.Arg953*	stop_gained	Exon 7 of 7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1 link	c.3142C>T	p.Arg1048*	stop_gained	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.2755C>T	p.Arg919*	stop_gained	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*3062C>T		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 link	c.2857C>T	p.Arg953*	stop_gained	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251340

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112012

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000170

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 31, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation, as the last 509 amino acid(s) are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 22847150, 25326635, 24011642, 11133365, 31589614, 32376792, 36623372) -

Mar 11, 2019

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -

Jan 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Pathogenic:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PRX-related disorder

Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PRX c.2857C>T variant is predicted to result in premature protein termination (p.Arg953*). This variant was reported in individuals with Charcot-Marie-Tooth Disease (homozygous, Castoro et al 2022. PubMed ID: 36623372; unspecified zygosity, Volodarsky et al. 2020. PubMed ID: 32376792) as well as in the compound heterozygous state in an individual with Dejerine-Sottas syndrome and in the heterozygous state in her unaffected son (Boerkoel et al. 2001. PubMed ID: 11133365). This variant is predicted to cause loss of normal protein function through the loss of the last 509 amino acids of the Periaxin protein, and other loss-of-function variants have been reported downstream of this variant (https://www.ncbi.nlm.nih.gov/clinvar; Human Gene Mutation Database (HGMD)). Nonsense variants in PRX are expected to be pathogenic. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Charcot-Marie-Tooth disease type 4F

Pathogenic:1

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 14-year-old female with Charcot Marie Tooth disease. Heterozygotes are expected to be asymptomatic carriers. -

Charcot-Marie-Tooth disease type 4

Pathogenic:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg953*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 509 amino acid(s) of the PRX protein. This variant is present in population databases (rs104894714, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Dejerine-Sottas syndrome (PMID: 11133365). ClinVar contains an entry for this variant (Variation ID: 4787). This variant disrupts a region of the PRX protein in which other variant(s) (p.R1070*) have been determined to be pathogenic (PMID: 15197604, 16770524, 22847150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive Dejerine-Sottas syndrome

Pathogenic:1

Feb 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.063

PhyloP100

0.65

Vest4

0.70

GERP RS

3.8

Mutation Taster

=24/176

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over