19-40397621-G-A

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.731C>T(p.Ala244Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,541,072 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A244S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 31 hom., cov: 33)

Exomes 𝑓: 0.018 ( 279 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.591

Publications

8 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=0.0023050308).

BP6

Variant 19-40397621-G-A is Benign according to our data. Variant chr19-40397621-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138817.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 = 0.0136 (2065/152304) while in subpopulation NFE AF = 0.021 (1427/68004). AF 95% confidence interval is 0.0201. There are 31 homozygotes in GnomAd4. There are 987 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3 link	c.731C>T	p.Ala244Val	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 link	c.1016C>T	p.Ala339Val	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.629C>T	p.Ala210Val	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*936C>T		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.731C>T	p.Ala244Val	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2066

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0244

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0128

AC:

1753

AN:

137004

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.00359

Gnomad AMR exome

AF:

0.00718

Gnomad ASJ exome

AF:

0.0183

Gnomad EAS exome

AF:

0.0000908

Gnomad FIN exome

AF:

0.0217

Gnomad NFE exome

AF:

0.0221

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0182

AC:

25278

AN:

1388768

Hom.:

279

Cov.:

AF XY:

0.0178

AC XY:

12195

AN XY:

685704

show subpopulations

African (AFR)

AF:

0.00267

AC:

AN:

31854

American (AMR)

AF:

0.00718

AC:

258

AN:

35950

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

487

AN:

25172

East Asian (EAS)

AF:

0.0000553

AC:

AN:

36186

South Asian (SAS)

AF:

0.00157

AC:

125

AN:

79458

European-Finnish (FIN)

AF:

0.0201

AC:

732

AN:

36398

Middle Eastern (MID)

AF:

0.0143

AC:

AN:

5040

European-Non Finnish (NFE)

AF:

0.0211

AC:

22758

AN:

1080784

Other (OTH)

AF:

0.0131

AC:

759

AN:

57926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1774

3548

5322

7096

8870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

848

1696

2544

3392

4240

<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:

0.0136

AC:

2065

AN:

152304

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

987

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00293

AC:

122

AN:

41584

American (AMR)

AF:

0.00752

AC:

115

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0244

AC:

259

AN:

10630

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0210

AC:

1427

AN:

68004

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00990

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00257

AC:

ESP6500EA

AF:

0.0156

AC:

113

ExAC

AF:

0.00794

AC:

855

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

Apr 24, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 02, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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 4F

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

0.092

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.079

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

PhyloP100

0.59

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.090

REVEL

Benign

0.066

Sift

Benign

0.40

Sift4G

Uncertain

0.021

Polyphen

0.095

Vest4

0.11

MPC

0.61

ClinPred

0.0095

GERP RS

3.6

Varity_R

0.040

gMVP

0.37

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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