rs744389

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_181882.3(PRX):c.306C>T(p.Thr102Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,946 control chromosomes in the GnomAD database, including 25,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1514 hom., cov: 32)

Exomes 𝑓: 0.17 ( 24019 hom. )

Consequence

PRX
NM_181882.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.250

Publications

16 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 19-40398695-G-A is Benign according to our data. Variant chr19-40398695-G-A is described in ClinVar as Benign. ClinVar VariationId is 130051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PRX	NM_181882.3 link	c.306C>T	p.Thr102Thr	synonymous_variant	Exon 6 of 7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1 link	c.591C>T	p.Thr197Thr	synonymous_variant	Exon 6 of 7		NP_001398056.1
PRX	NM_020956.2 link	c.306C>T	p.Thr102Thr	synonymous_variant	Exon 6 of 6		NP_066007.1
PRX	XM_017027047.2 link	c.204C>T	p.Thr68Thr	synonymous_variant	Exon 3 of 4		XP_016882536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 link	c.306C>T	p.Thr102Thr	synonymous_variant	Exon 6 of 7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19172

AN:

152106

Hom.:

1515

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0413

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.0949

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0356

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.122

GnomAD2 exomes

AF:

0.140

AC:

35121

AN:

250146

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.0716

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.0308

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.151

GnomAD4 exome

AF:

0.175

AC:

255736

AN:

1461722

Hom.:

24019

Cov.:

AF XY:

0.175

AC XY:

127596

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0325

AC:

1087

AN:

33476

American (AMR)

AF:

0.0747

AC:

3339

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0981

AC:

2562

AN:

26126

East Asian (EAS)

AF:

0.0226

AC:

896

AN:

39694

South Asian (SAS)

AF:

0.188

AC:

16179

AN:

86256

European-Finnish (FIN)

AF:

0.144

AC:

7663

AN:

53372

Middle Eastern (MID)

AF:

0.114

AC:

655

AN:

5768

European-Non Finnish (NFE)

AF:

0.192

AC:

213693

AN:

1111930

Other (OTH)

AF:

0.160

AC:

9662

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

15197

30394

45591

60788

75985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7366

14732

22098

29464

36830

<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:

0.126

AC:

19167

AN:

152224

Hom.:

1514

Cov.:

AF XY:

0.123

AC XY:

9147

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0412

AC:

1711

AN:

41552

American (AMR)

AF:

0.0947

AC:

1448

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

368

AN:

3472

East Asian (EAS)

AF:

0.0351

AC:

182

AN:

5184

South Asian (SAS)

AF:

0.189

AC:

910

AN:

4820

European-Finnish (FIN)

AF:

0.138

AC:

1461

AN:

10608

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12626

AN:

67984

Other (OTH)

AF:

0.121

AC:

256

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

872

1743

2615

3486

4358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.155

Hom.:

3273

Bravo

AF:

0.116

Asia WGS

AF:

0.0870

AC:

303

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.179

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Mar 20, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inherited Neuropathy Consortium

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Charcot-Marie-Tooth disease type 4F

Benign:2

Apr 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

0.25

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

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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