rs268673

Positions:

chr19-40395589-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181882.3(PRX):c.2763A>G(p.Ile921Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,613,966 control chromosomes in the GnomAD database, including 120,371 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 Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 9923 hom., cov: 32)

Exomes 𝑓: 0.38 ( 110448 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.87

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=8.197129E-4).

BP6

Variant 19-40395589-T-C is Benign according to our data. Variant chr19-40395589-T-C is described in ClinVar as [Benign]. Clinvar id is 130050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40395589-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRX	NM_181882.3 linkuse as main transcript	c.2763A>G	p.Ile921Met	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1 linkuse as main transcript	c.3048A>G	p.Ile1016Met	missense_variant	7/7
PRX	XM_017027047.2 linkuse as main transcript	c.2661A>G	p.Ile887Met	missense_variant	4/4
PRX	NM_020956.2 linkuse as main transcript	c.*2968A>G		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.2763A>G	p.Ile921Met	missense_variant	7/7	1	NM_181882.3	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54244

AN:

151964

Hom.:

9920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.323

Gnomad AMI

AF:

0.515

Gnomad AMR

AF:

0.386

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.249

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.362

GnomAD3 exomes

AF:

0.352

AC:

88588

AN:

251422

Hom.:

16531

AF XY:

0.348

AC XY:

47271

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.321

Gnomad AMR exome

AF:

0.432

Gnomad ASJ exome

AF:

0.339

Gnomad EAS exome

AF:

0.145

Gnomad SAS exome

AF:

0.249

Gnomad FIN exome

AF:

0.351

Gnomad NFE exome

AF:

0.395

Gnomad OTH exome

AF:

0.358

GnomAD4 exome

AF:

0.383

AC:

560481

AN:

1461884

Hom.:

110448

Cov.:

AF XY:

0.379

AC XY:

275536

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.316

Gnomad4 AMR exome

AF:

0.426

Gnomad4 ASJ exome

AF:

0.332

Gnomad4 EAS exome

AF:

0.130

Gnomad4 SAS exome

AF:

0.250

Gnomad4 FIN exome

AF:

0.346

Gnomad4 NFE exome

AF:

0.408

Gnomad4 OTH exome

AF:

0.363

GnomAD4 genome

AF:

0.357

AC:

54269

AN:

152082

Hom.:

9923

Cov.:

AF XY:

0.351

AC XY:

26082

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.323

Gnomad4 AMR

AF:

0.386

Gnomad4 ASJ

AF:

0.327

Gnomad4 EAS

AF:

0.147

Gnomad4 SAS

AF:

0.249

Gnomad4 FIN

AF:

0.345

Gnomad4 NFE

AF:

0.396

Gnomad4 OTH

AF:

0.357

Alfa

AF:

0.371

Hom.:

22379

Bravo

AF:

0.364

TwinsUK

AF:

0.411

AC:

1523

ALSPAC

AF:

0.410

AC:

1582

ESP6500AA

AF:

0.324

AC:

1428

ESP6500EA

AF:

0.388

AC:

3336

ExAC

AF:

0.350

AC:

42527

Asia WGS

AF:

0.183

AC:

638

AN:

3478

EpiCase

AF:

0.373

EpiControl

AF:

0.389

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Charcot-Marie-Tooth disease type 4F

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 25, 2017	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.039

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0070

DANN

Benign

0.29

DEOGEN2

Benign

0.045

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.15

MetaRNN

Benign

0.00082

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.8

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

0.58

REVEL

Benign

0.027

Sift

Benign

0.32

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.0060

MPC

0.23

ClinPred

0.011

GERP RS

-5.4

Varity_R

0.054

gMVP

0.060

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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