19-40394958-C-T

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.3394G>A(p.Gly1132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,608,036 control chromosomes in the GnomAD database, including 716,680 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1132G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.96 ( 69595 hom., cov: 32)

Exomes 𝑓: 0.94 ( 647085 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.347

Publications

43 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=9.3784814E-7).

BP6

Variant 19-40394958-C-T is Benign according to our data. Variant chr19-40394958-C-T is described in ClinVar as Benign. ClinVar VariationId is 130053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PRX	NM_181882.3 link	c.3394G>A	p.Gly1132Arg	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1 link	c.3679G>A	p.Gly1227Arg	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.3292G>A	p.Gly1098Arg	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*3599G>A		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.3394G>A	p.Gly1132Arg	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes

AF:

0.956

AC:

145384

AN:

152112

Hom.:

69535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.989

Gnomad AMI

AF:

0.866

Gnomad AMR

AF:

0.956

Gnomad ASJ

AF:

0.954

Gnomad EAS

AF:

0.978

Gnomad SAS

AF:

0.925

Gnomad FIN

AF:

0.943

Gnomad MID

AF:

0.892

Gnomad NFE

AF:

0.940

Gnomad OTH

AF:

0.943

GnomAD2 exomes

AF:

0.946

AC:

234284

AN:

247592

AF XY:

0.943

show subpopulations

Gnomad AFR exome

AF:

0.991

Gnomad AMR exome

AF:

0.955

Gnomad ASJ exome

AF:

0.944

Gnomad EAS exome

AF:

0.979

Gnomad FIN exome

AF:

0.941

Gnomad NFE exome

AF:

0.940

Gnomad OTH exome

AF:

0.938

GnomAD4 exome

AF:

0.943

AC:

1372357

AN:

1455806

Hom.:

647085

Cov.:

AF XY:

0.941

AC XY:

681552

AN XY:

724130

show subpopulations

African (AFR)

AF:

0.991

AC:

33152

AN:

33450

American (AMR)

AF:

0.955

AC:

42693

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.946

AC:

24719

AN:

26126

East Asian (EAS)

AF:

0.981

AC:

38908

AN:

39642

South Asian (SAS)

AF:

0.918

AC:

79194

AN:

86240

European-Finnish (FIN)

AF:

0.942

AC:

45959

AN:

48784

Middle Eastern (MID)

AF:

0.908

AC:

5232

AN:

5762

European-Non Finnish (NFE)

AF:

0.941

AC:

1045475

AN:

1110838

Other (OTH)

AF:

0.946

AC:

57025

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

5716

11432

17147

22863

28579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21596

43192

64788

86384

107980

<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:

0.956

AC:

145502

AN:

152230

Hom.:

69595

Cov.:

AF XY:

0.956

AC XY:

71110

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.989

AC:

41123

AN:

41560

American (AMR)

AF:

0.956

AC:

14627

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.954

AC:

3311

AN:

3472

East Asian (EAS)

AF:

0.978

AC:

5030

AN:

5144

South Asian (SAS)

AF:

0.925

AC:

4458

AN:

4822

European-Finnish (FIN)

AF:

0.943

AC:

9999

AN:

10600

Middle Eastern (MID)

AF:

0.888

AC:

261

AN:

294

European-Non Finnish (NFE)

AF:

0.940

AC:

63910

AN:

68012

Other (OTH)

AF:

0.944

AC:

1995

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

338

676

1014

1352

1690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.943

Hom.:

132429

Bravo

AF:

0.958

TwinsUK

AF:

0.944

AC:

3499

ALSPAC

AF:

0.949

AC:

3656

ESP6500AA

AF:

0.989

AC:

4358

ESP6500EA

AF:

0.936

AC:

8047

ExAC

AF:

0.947

AC:

114939

Asia WGS

AF:

0.956

AC:

3325

AN:

3478

EpiCase

AF:

0.926

EpiControl

AF:

0.932

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

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. -

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease type 4F

Benign:2

Oct 25, 2021

Genome-Nilou Lab

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

- -

Dejerine-Sottas disease

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Feb 04, 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

0.065

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.6

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.076

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0081

LIST_S2

Benign

0.35

MetaRNN

Benign

9.4e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.63

PhyloP100

-0.35

PrimateAI

Benign

0.33

PROVEAN

Benign

0.79

REVEL

Benign

0.036

Sift

Benign

0.13

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.018

MutPred

0.43

Gain of solvent accessibility (P = 0.0097);

MPC

0.27

ClinPred

0.0036

GERP RS

3.6

Varity_R

0.050

gMVP

0.078

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