rs10425452

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_181882.3(PRX):c.499C>T(p.Arg167Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,604,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.64

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 4
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 4F
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
Charcot-Marie-Tooth disease type 3
Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

PRX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03500694).

BP6

Variant 19-40397853-G-A is Benign according to our data. Variant chr19-40397853-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448141.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000558 (85/152364) while in subpopulation AFR AF = 0.00183 (76/41600). AF 95% confidence interval is 0.0015. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3 link	c.499C>T	p.Arg167Cys	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 link	c.784C>T	p.Arg262Cys	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.397C>T	p.Arg133Cys	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*704C>T		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1	Q9BXM0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 link	c.499C>T	p.Arg167Cys	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000159

AC:

AN:

226454

AF XY:

0.0000728

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.000156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000514

Gnomad NFE exome

AF:

0.0000597

Gnomad OTH exome

AF:

0.000543

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1451714

Hom.:

Cov.:

AF XY:

0.0000915

AC XY:

AN XY:

721426

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33420

American (AMR)

AF:

0.000164

AC:

AN:

42660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25822

East Asian (EAS)

AF:

0.00

AC:

AN:

39426

South Asian (SAS)

AF:

0.00

AC:

AN:

84720

European-Finnish (FIN)

AF:

0.000115

AC:

AN:

52240

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000677

AC:

AN:

1107722

Other (OTH)

AF:

0.000284

AC:

AN:

59952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000558

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41600

American (AMR)

AF:

0.000261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000282

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.000912

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.499C>T (p.R167C) alteration is located in exon 7 (coding exon 4) of the PRX gene. This alteration results from a C to T substitution at nucleotide position 499, causing the arginine (R) at amino acid position 167 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Feb 09, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.014

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

PhyloP100

2.6

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.14

Sift

Benign

0.041

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.47

MVP

0.45

MPC

0.85

ClinPred

0.044

GERP RS

4.7

Varity_R

0.13

gMVP

0.60

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over