rs117336941

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181882.3(PRX):c.1216G>A(p.Ala406Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,614,152 control chromosomes in the GnomAD database, including 54 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 45 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.733

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028489232).

BP6

Variant 19-40397136-C-T is Benign according to our data. Variant chr19-40397136-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220724.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=1}. Variant chr19-40397136-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00445 (678/152330) while in subpopulation NFE AF= 0.00612 (416/68024). AF 95% confidence interval is 0.00563. There are 9 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3 link	c.1216G>A	p.Ala406Thr	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 link	c.1501G>A	p.Ala501Thr	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.1114G>A	p.Ala372Thr	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*1421G>A		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.1216G>A	p.Ala406Thr	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.00445

AC:

678

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00611

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00451

AC:

1131

AN:

250982

Hom.:

AF XY:

0.00457

AC XY:

621

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00785

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.00564

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00557

AC:

8136

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

4046

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00723

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0147

Gnomad4 NFE exome

AF:

0.00614

Gnomad4 OTH exome

AF:

0.00429

GnomAD4 genome

AF:

0.00445

AC:

678

AN:

152330

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

332

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0162

Gnomad4 NFE

AF:

0.00612

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00586

Hom.:

Bravo

AF:

0.00314

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00453

AC:

550

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRX: BP4, BS2 -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4F

Uncertain:1Benign:1

May 23, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

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

- -

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 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

0.066

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.20

DANN

Benign

0.63

DEOGEN2

Benign

0.087

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.46

PrimateAI

Benign

0.36

PROVEAN

Benign

0.060

REVEL

Benign

0.042

Sift

Benign

0.23

Sift4G

Benign

0.10

Polyphen

0.0070

Vest4

0.13

MVP

0.085

MPC

0.22

ClinPred

0.0021

GERP RS

-3.2

Varity_R

0.035

gMVP

0.075

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