Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181882.3(PRX):c.1964C>T(p.Pro655Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,613,766 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P655P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00079 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00064 ( 6 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.07

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034578443).

BP6

Variant 19-40396388-G-A is Benign according to our data. Variant chr19-40396388-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00079 (120/151952) while in subpopulation EAS AF = 0.0216 (111/5138). AF 95% confidence interval is 0.0183. There are 3 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRX	NM_181882.3	MANE Select	c.1964C>T	p.Pro655Leu	missense	Exon 7 of 7	NP_870998.2
PRX	NM_001411127.1		c.2249C>T	p.Pro750Leu	missense	Exon 7 of 7	NP_001398056.1
PRX	NM_020956.2		c.*2169C>T		3_prime_UTR	Exon 6 of 6	NP_066007.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRX	ENST00000324001.8	TSL:1 MANE Select	c.1964C>T	p.Pro655Leu	missense	Exon 7 of 7	ENSP00000326018.6
PRX	ENST00000291825.11	TSL:1	c.*2169C>T		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6
PRX	ENST00000674005.2		c.2249C>T	p.Pro750Leu	missense	Exon 7 of 7	ENSP00000501261.1

Frequencies

GnomAD3 genomes

AF:

0.000790

AC:

120

AN:

151836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0216

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00204

AC:

513

AN:

251004

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.000313

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0275

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000637

AC:

931

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

432

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0220

AC:

875

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111990

Other (OTH)

AF:

0.000762

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000790

AC:

120

AN:

151952

Hom.:

Cov.:

AF XY:

0.000727

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41416

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0216

AC:

111

AN:

5138

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000893

Hom.:

Bravo

AF:

0.000907

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00200

AC:

243

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

Charcot-Marie-Tooth disease type 4F (1)

Dejerine-Sottas disease;C3540453:Charcot-Marie-Tooth disease type 4F (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.6

PhyloP100

1.1

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.078

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0030

Polyphen

0.093

Vest4

0.24

MVP

0.55

MPC

0.74

ClinPred

0.060

GERP RS

3.9

Varity_R

0.11

gMVP

0.42

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs118003416

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over