rs744389

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

2

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]

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 UniProt
PRXNM_181882.3 linkuse as main transcriptc.306C>T p.Thr102= synonymous_variant 6/7 ENST00000324001.8 NP_870998.2
PRXNM_001411127.1 linkuse as main transcriptc.591C>T p.Thr197= synonymous_variant 6/7 NP_001398056.1
PRXNM_020956.2 linkuse as main transcriptc.306C>T p.Thr102= synonymous_variant 6/6 NP_066007.1
PRXXM_017027047.2 linkuse as main transcriptc.204C>T p.Thr68= synonymous_variant 3/4 XP_016882536.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRXENST00000324001.8 linkuse as main transcriptc.306C>T p.Thr102= synonymous_variant 6/71 NM_181882.3 ENSP00000326018 A2Q9BXM0-1

Frequencies

GnomAD3 genomes
AF:
0.126
AC:
19172
AN:
152106
Hom.:
1515
Cov.:
32
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.:
36
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.:
32
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 providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 20, 2014This 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 providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedliterature onlyInherited Neuropathy Consortium-- -
Likely benign, no assertion criteria providedclinical testingGenetic 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 providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Charcot-Marie-Tooth disease type 4F Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingAthena DiagnosticsApr 25, 2017- -
Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Charcot-Marie-Tooth disease type 4 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
CADD
Benign
11
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.

Other links and lift over

dbSNP: rs744389; hg19: chr19-40904602; COSMIC: COSV52532202; API