chr19-40395104-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181882.3(PRX):c.3248C>G(p.Pro1083Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,640 control chromosomes in the GnomAD database, including 24,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1083L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1480 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23458 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.76

Publications

30 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014650226).

BP6

Variant 19-40395104-G-C is Benign according to our data. Variant chr19-40395104-G-C is described in ClinVar as Benign. ClinVar VariationId is 130052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3 link	c.3248C>G	p.Pro1083Arg	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 link	c.3533C>G	p.Pro1178Arg	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.3146C>G	p.Pro1049Arg	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*3453C>G		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1	Q9BXM0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 link	c.3248C>G	p.Pro1083Arg	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18906

AN:

151950

Hom.:

1481

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0411

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.0917

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0352

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.121

GnomAD2 exomes

AF:

0.137

AC:

34384

AN:

251006

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.0363

Gnomad AMR exome

AF:

0.0701

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.0307

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.181

Gnomad OTH exome

AF:

0.148

GnomAD4 exome

AF:

0.173

AC:

252568

AN:

1461572

Hom.:

23458

Cov.:

AF XY:

0.173

AC XY:

125616

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0323

AC:

1082

AN:

33478

American (AMR)

AF:

0.0730

AC:

3265

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0978

AC:

2555

AN:

26136

East Asian (EAS)

AF:

0.0224

AC:

891

AN:

39700

South Asian (SAS)

AF:

0.168

AC:

14464

AN:

86258

European-Finnish (FIN)

AF:

0.144

AC:

7627

AN:

53138

Middle Eastern (MID)

AF:

0.107

AC:

618

AN:

5768

European-Non Finnish (NFE)

AF:

0.191

AC:

212509

AN:

1111984

Other (OTH)

AF:

0.158

AC:

9557

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

15975

31949

47924

63898

79873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7322

14644

21966

29288

36610

<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:

0.124

AC:

18901

AN:

152068

Hom.:

1480

Cov.:

AF XY:

0.121

AC XY:

8999

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0410

AC:

1702

AN:

41496

American (AMR)

AF:

0.0916

AC:

1398

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

367

AN:

3470

East Asian (EAS)

AF:

0.0347

AC:

179

AN:

5164

South Asian (SAS)

AF:

0.172

AC:

828

AN:

4814

European-Finnish (FIN)

AF:

0.138

AC:

1455

AN:

10576

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.184

AC:

12517

AN:

67962

Other (OTH)

AF:

0.119

AC:

252

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

842

1685

2527

3370

4212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

206

412

618

824

1030

<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:

0.152

Hom.:

1530

Bravo

AF:

0.115

TwinsUK

AF:

0.201

AC:

745

ALSPAC

AF:

0.199

AC:

768

ESP6500AA

AF:

0.0431

AC:

190

ESP6500EA

AF:

0.179

AC:

1542

ExAC

AF:

0.141

AC:

17101

Asia WGS

AF:

0.0810

AC:

281

AN:

3478

EpiCase

AF:

0.170

EpiControl

AF:

0.177

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4F

Benign:2

Apr 26, 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

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

1.8

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.3

REVEL

Benign

0.064

Sift

Benign

0.11

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.11

MPC

0.82

ClinPred

0.024

GERP RS

1.3

Varity_R

0.049

gMVP

0.075

Mutation Taster

=97/3

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