19-40396515-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181882.3(PRX):​c.1837G>A​(p.Val613Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.878

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1279231).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRXNM_181882.3 linkc.1837G>A p.Val613Met missense_variant Exon 7 of 7 ENST00000324001.8 NP_870998.2 Q9BXM0-1
PRXNM_001411127.1 linkc.2122G>A p.Val708Met missense_variant Exon 7 of 7 NP_001398056.1
PRXXM_017027047.2 linkc.1735G>A p.Val579Met missense_variant Exon 4 of 4 XP_016882536.1
PRXNM_020956.2 linkc.*2042G>A 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
PRXENST00000324001.8 linkc.1837G>A p.Val613Met missense_variant Exon 7 of 7 1 NM_181882.3 ENSP00000326018.6 Q9BXM0-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152126
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000478
AC:
12
AN:
250942
AF XY:
0.0000589
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000529
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461776
Hom.:
0
Cov.:
37
AF XY:
0.0000399
AC XY:
29
AN XY:
727180
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33470
American (AMR)
AF:
0.000179
AC:
8
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86204
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000324
AC:
36
AN:
1111974
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152126
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74312
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41408
American (AMR)
AF:
0.00
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000772
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 01, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

BP4 -

Charcot-Marie-Tooth disease type 4 Uncertain:1
Oct 13, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 613 of the PRX protein (p.Val613Met). This variant is present in population databases (rs773222045, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 216833). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T
Eigen
Benign
0.044
Eigen_PC
Benign
-0.071
FATHMM_MKL
Benign
0.057
N
LIST_S2
Benign
0.72
T
M_CAP
Benign
0.0099
T
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.8
L
PhyloP100
-0.88
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.33
N
REVEL
Benign
0.066
Sift
Benign
0.26
T
Sift4G
Benign
0.10
T
Polyphen
0.98
D
Vest4
0.19
MVP
0.36
MPC
0.68
ClinPred
0.11
T
GERP RS
3.4
Varity_R
0.053
gMVP
0.073
Mutation Taster
=85/15
polymorphism

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

Other links and lift over

dbSNP: rs773222045; hg19: chr19-40902422; API