rs73933276

Positions:

Variant summary

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

The NM_181882.3(PRX):c.1051C>T(p.Pro351Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0037 in 1,613,266 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 94 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 89 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.78

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=0.005027175).

BP6

Variant 19-40397301-G-A is Benign according to our data. Variant chr19-40397301-G-A is described in ClinVar as [Benign]. Clinvar id is 220690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40397301-G-A is described in Lovd as [Benign]. Variant chr19-40397301-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3 linkuse as main transcript	c.1051C>T	p.Pro351Ser	missense_variant	7/7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 linkuse as main transcript	c.1336C>T	p.Pro446Ser	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2 linkuse as main transcript	c.949C>T	p.Pro317Ser	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2 linkuse as main transcript	c.*1256C>T		3_prime_UTR_variant	6/6		NP_066007.1	Q9BXM0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.1051C>T	p.Pro351Ser	missense_variant	7/7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2893

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0664

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00507

AC:

1254

AN:

247290

Hom.:

AF XY:

0.00377

AC XY:

507

AN XY:

134656

show subpopulations

Gnomad AFR exome

AF:

0.0672

Gnomad AMR exome

AF:

0.00458

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00313

GnomAD4 exome

AF:

0.00210

AC:

3070

AN:

1461024

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1331

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.0674

Gnomad4 AMR exome

AF:

0.00474

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000284

Gnomad4 OTH exome

AF:

0.00429

GnomAD4 genome

AF:

0.0190

AC:

2896

AN:

152242

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0663

Gnomad4 AMR

AF:

0.00628

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00861

Hom.:

Bravo

AF:

0.0223

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0655

AC:

288

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00634

AC:

769

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 4F

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.7

REVEL

Benign

0.20

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.54

MVP

0.64

MPC

0.69

ClinPred

0.058

GERP RS

4.6

Varity_R

0.40

gMVP

0.28

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