19-40395697-A-G

Position:

chr19-40395697-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_181882.3(PRX):c.2655T>C(p.Pro885=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,613,490 control chromosomes in the GnomAD database, including 230,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 27124 hom., cov: 33)

Exomes 𝑓: 0.52 ( 203248 hom. )

Consequence

PRX
NM_181882.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -3.17

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 19-40395697-A-G is Benign according to our data. Variant chr19-40395697-A-G is described in ClinVar as [Benign]. Clinvar id is 130049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40395697-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRX	NM_181882.3 linkuse as main transcript	c.2655T>C	p.Pro885=	synonymous_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1 linkuse as main transcript	c.2940T>C	p.Pro980=	synonymous_variant	7/7
PRX	XM_017027047.2 linkuse as main transcript	c.2553T>C	p.Pro851=	synonymous_variant	4/4
PRX	NM_020956.2 linkuse as main transcript	c.*2860T>C		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.2655T>C	p.Pro885=	synonymous_variant	7/7	1	NM_181882.3	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.579

AC:

87698

AN:

151590

Hom.:

27082

Cov.:

show subpopulations

Gnomad AFR

AF:

0.800

Gnomad AMI

AF:

0.652

Gnomad AMR

AF:

0.517

Gnomad ASJ

AF:

0.446

Gnomad EAS

AF:

0.203

Gnomad SAS

AF:

0.467

Gnomad FIN

AF:

0.445

Gnomad MID

AF:

0.452

Gnomad NFE

AF:

0.522

Gnomad OTH

AF:

0.552

GnomAD3 exomes

AF:

0.500

AC:

125454

AN:

250912

Hom.:

33050

AF XY:

0.495

AC XY:

67162

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.805

Gnomad AMR exome

AF:

0.519

Gnomad ASJ exome

AF:

0.470

Gnomad EAS exome

AF:

0.195

Gnomad SAS exome

AF:

0.474

Gnomad FIN exome

AF:

0.454

Gnomad NFE exome

AF:

0.519

Gnomad OTH exome

AF:

0.495

GnomAD4 exome

AF:

0.521

AC:

762106

AN:

1461782

Hom.:

203248

Cov.:

AF XY:

0.519

AC XY:

377289

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.801

Gnomad4 AMR exome

AF:

0.519

Gnomad4 ASJ exome

AF:

0.462

Gnomad4 EAS exome

AF:

0.184

Gnomad4 SAS exome

AF:

0.472

Gnomad4 FIN exome

AF:

0.450

Gnomad4 NFE exome

AF:

0.534

Gnomad4 OTH exome

AF:

0.514

GnomAD4 genome

AF:

0.579

AC:

87787

AN:

151708

Hom.:

27124

Cov.:

AF XY:

0.569

AC XY:

42172

AN XY:

74120

show subpopulations

Gnomad4 AFR

AF:

0.800

Gnomad4 AMR

AF:

0.517

Gnomad4 ASJ

AF:

0.446

Gnomad4 EAS

AF:

0.201

Gnomad4 SAS

AF:

0.467

Gnomad4 FIN

AF:

0.445

Gnomad4 NFE

AF:

0.522

Gnomad4 OTH

AF:

0.544

Alfa

AF:

0.517

Hom.:

17461

Bravo

AF:

0.596

Asia WGS

AF:

0.337

AC:

1173

AN:

3478

EpiCase

AF:

0.509

EpiControl

AF:

0.522

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	-	- -
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. -

Charcot-Marie-Tooth disease type 4F

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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. -

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

- -

Dejerine-Sottas disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.14

DANN

Benign

0.31

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