rs146789340

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181882.3(PRX):c.1483G>C(p.Glu495Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,575,062 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 128 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.113

Publications

12 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=0.00758934).

BP6

Variant 19-40396869-C-G is Benign according to our data. Variant chr19-40396869-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0107 (1493/138960) while in subpopulation NFE AF = 0.0143 (912/63802). AF 95% confidence interval is 0.0135. There are 12 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PRX	NM_181882.3 link	c.1483G>C	p.Glu495Gln	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1 link	c.1768G>C	p.Glu590Gln	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.1381G>C	p.Glu461Gln	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*1688G>C		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.1483G>C	p.Glu495Gln	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1494

AN:

138882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00330

Gnomad AMI

AF:

0.00254

Gnomad AMR

AF:

0.00824

Gnomad ASJ

AF:

0.0116

Gnomad EAS

AF:

0.000220

Gnomad SAS

AF:

0.0134

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.0165

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0121

GnomAD2 exomes

AF:

0.00508

AC:

1255

AN:

247112

AF XY:

0.00515

show subpopulations

Gnomad AFR exome

AF:

0.00113

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00345

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.00627

Gnomad OTH exome

AF:

0.00824

GnomAD4 exome

AF:

0.00686

AC:

9847

AN:

1436102

Hom.:

128

Cov.:

AF XY:

0.00717

AC XY:

5128

AN XY:

714974

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33212

American (AMR)

AF:

0.00368

AC:

162

AN:

44054

Ashkenazi Jewish (ASJ)

AF:

0.00743

AC:

190

AN:

25568

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.00755

AC:

644

AN:

85292

European-Finnish (FIN)

AF:

0.0177

AC:

936

AN:

52982

Middle Eastern (MID)

AF:

0.00367

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00678

AC:

7398

AN:

1090352

Other (OTH)

AF:

0.00763

AC:

453

AN:

59404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

564

1128

1691

2255

2819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.0107

AC:

1493

AN:

138960

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

739

AN XY:

67844

show subpopulations

African (AFR)

AF:

0.00329

AC:

122

AN:

37040

American (AMR)

AF:

0.00823

AC:

115

AN:

13968

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

AN:

3284

East Asian (EAS)

AF:

0.000221

AC:

AN:

4526

South Asian (SAS)

AF:

0.0134

AC:

AN:

4254

European-Finnish (FIN)

AF:

0.0240

AC:

220

AN:

9162

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.0143

AC:

912

AN:

63802

Other (OTH)

AF:

0.0120

AC:

AN:

1910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

135

203

270

338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0139

Hom.:

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0165

AC:

142

ExAC

AF:

0.00283

AC:

343

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRX: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4F

Benign:2

May 19, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

- -

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

0.072

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.085

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.074

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.60

PhyloP100

-0.11

PrimateAI

Benign

0.33

PROVEAN

Benign

0.030

REVEL

Benign

0.020

Sift

Benign

0.41

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.070

MVP

0.22

MPC

0.22

ClinPred

0.00034

GERP RS

-3.1

Varity_R

0.063

gMVP

0.076

Mutation Taster

=96/4

polymorphism

(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