19-40397633-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_181882.3(PRX):c.719G>A(p.Arg240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,543,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.244

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057433546).

BP6

Variant 19-40397633-C-T is Benign according to our data. Variant chr19-40397633-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476979.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00126 (192/152318) while in subpopulation AFR AF = 0.00442 (184/41590). AF 95% confidence interval is 0.0039. There are 0 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRX	NM_181882.3	MANE Select	c.719G>A	p.Arg240Gln	missense	Exon 7 of 7	NP_870998.2
PRX	NM_001411127.1		c.1004G>A	p.Arg335Gln	missense	Exon 7 of 7	NP_001398056.1
PRX	NM_020956.2		c.*924G>A		3_prime_UTR	Exon 6 of 6	NP_066007.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRX	ENST00000324001.8	TSL:1 MANE Select	c.719G>A	p.Arg240Gln	missense	Exon 7 of 7	ENSP00000326018.6
PRX	ENST00000291825.11	TSL:1	c.*924G>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6
PRX	ENST00000674005.2		c.1004G>A	p.Arg335Gln	missense	Exon 7 of 7	ENSP00000501261.1

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00444

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000314

AC:

AN:

140038

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000240

GnomAD4 exome

AF:

0.000145

AC:

201

AN:

1390822

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

686936

show subpopulations

African (AFR)

AF:

0.00474

AC:

152

AN:

32034

American (AMR)

AF:

0.0000831

AC:

AN:

36094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.0000275

AC:

AN:

36416

South Asian (SAS)

AF:

0.000327

AC:

AN:

79576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5204

European-Non Finnish (NFE)

AF:

0.00000555

AC:

AN:

1081856

Other (OTH)

AF:

0.000224

AC:

AN:

58046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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

AF:

0.00126

AC:

192

AN:

152318

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00442

AC:

184

AN:

41590

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000467

Hom.:

Bravo

AF:

0.00150

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000317

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4F

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not specified

Benign:1

May 07, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Sep 19, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided

Benign:1

Apr 09, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease type 4

Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.73

M_CAP

Benign

0.0041

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

PhyloP100

0.24

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.61

REVEL

Benign

0.031

Sift

Benign

0.10

Sift4G

Benign

0.53

Polyphen

0.086

Vest4

0.11

MVP

0.25

MPC

0.48

ClinPred

0.010

GERP RS

-0.14

Varity_R

0.049

gMVP

0.27

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over