rs146789340

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 215545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40396869-C-G is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3 link	c.1483G>C	p.Glu495Gln	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
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	Q9BXM0-2

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		Q9BXM0-1

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

GnomAD3 exomes

AF:

0.00508

AC:

1255

AN:

247112

Hom.:

AF XY:

0.00515

AC XY:

688

AN XY:

133614

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 SAS exome

AF:

0.00333

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

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00368

Gnomad4 ASJ exome

AF:

0.00743

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00755

Gnomad4 FIN exome

AF:

0.0177

Gnomad4 NFE exome

AF:

0.00678

Gnomad4 OTH exome

AF:

0.00763

GnomAD4 genome

AF:

0.0107

AC:

1493

AN:

138960

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

739

AN XY:

67844

show subpopulations

Gnomad4 AFR

AF:

0.00329

Gnomad4 AMR

AF:

0.00823

Gnomad4 ASJ

AF:

0.0116

Gnomad4 EAS

AF:

0.000221

Gnomad4 SAS

AF:

0.0134

Gnomad4 FIN

AF:

0.0240

Gnomad4 NFE

AF:

0.0143

Gnomad4 OTH

AF:

0.0120

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 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

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over