rs744389

Positions:

chr19-40398695-G-A

Variant summary

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

The ENST00000324001.8(PRX):c.306C>T(p.Thr102=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,946 control chromosomes in the GnomAD database, including 25,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1514 hom., cov: 32)

Exomes 𝑓: 0.17 ( 24019 hom. )

Consequence

PRX
ENST00000324001.8 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.250

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=-0.49).

BP6

Variant 19-40398695-G-A is Benign according to our data. Variant chr19-40398695-G-A is described in ClinVar as [Benign]. Clinvar id is 130051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40398695-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PRX	NM_181882.3 linkuse as main transcript	c.306C>T	p.Thr102=	synonymous_variant	6/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1 linkuse as main transcript	c.591C>T	p.Thr197=	synonymous_variant	6/7		NP_001398056.1
PRX	NM_020956.2 linkuse as main transcript	c.306C>T	p.Thr102=	synonymous_variant	6/6		NP_066007.1
PRX	XM_017027047.2 linkuse as main transcript	c.204C>T	p.Thr68=	synonymous_variant	3/4		XP_016882536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.306C>T	p.Thr102=	synonymous_variant	6/7	1	NM_181882.3	ENSP00000326018	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19172

AN:

152106

Hom.:

1515

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0413

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.0949

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0356

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.122

GnomAD3 exomes

AF:

0.140

AC:

35121

AN:

250146

Hom.:

2951

AF XY:

0.148

AC XY:

20046

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.0716

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.0308

Gnomad SAS exome

AF:

0.190

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.151

GnomAD4 exome

AF:

0.175

AC:

255736

AN:

1461722

Hom.:

24019

Cov.:

AF XY:

0.175

AC XY:

127596

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0325

Gnomad4 AMR exome

AF:

0.0747

Gnomad4 ASJ exome

AF:

0.0981

Gnomad4 EAS exome

AF:

0.0226

Gnomad4 SAS exome

AF:

0.188

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.192

Gnomad4 OTH exome

AF:

0.160

GnomAD4 genome

AF:

0.126

AC:

19167

AN:

152224

Hom.:

1514

Cov.:

AF XY:

0.123

AC XY:

9147

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0412

Gnomad4 AMR

AF:

0.0947

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.0351

Gnomad4 SAS

AF:

0.189

Gnomad4 FIN

AF:

0.138

Gnomad4 NFE

AF:

0.186

Gnomad4 OTH

AF:

0.121

Alfa

AF:

0.160

Hom.:

2744

Bravo

AF:

0.116

Asia WGS

AF:

0.0870

AC:

303

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.179

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
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+	-	- -

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

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

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