rs748318191

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_181882.3(PRX):c.176T>C(p.Leu59Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000193 in 1,554,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.36

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRX	NM_181882.3 linkuse as main transcript	c.176T>C	p.Leu59Pro	missense_variant	5/7	ENST00000324001.8
PRX	NM_001411127.1 linkuse as main transcript	c.461T>C	p.Leu154Pro	missense_variant	5/7
PRX	NM_020956.2 linkuse as main transcript	c.176T>C	p.Leu59Pro	missense_variant	5/6
PRX	XM_017027047.2 linkuse as main transcript	c.-57T>C		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.176T>C	p.Leu59Pro	missense_variant	5/7	1	NM_181882.3	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1403272

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692568

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.24e-7

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73946

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000871

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 08, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRX-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces leucine with proline at codon 59 of the PRX protein (p.Leu59Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

D;T

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

-0.047

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.5

D;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.76

P;D

Vest4

0.84

MutPred

0.47

Loss of stability (P = 0.0304);Loss of stability (P = 0.0304);

MVP

0.81

MPC

0.38

ClinPred

0.99

GERP RS

4.2

Varity_R

0.90

gMVP

0.93

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