19-40394272-TTCCTCCTCCTCC-TTCCTCCTCCTCCTCC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_181882.3(PRX):c.4079_4080insGGA(p.Glu1360dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,605,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PRX
NM_181882.3 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.16

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 19-40394272-T-TTCC is Benign according to our data. Variant chr19-40394272-T-TTCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 699561.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRX	NM_181882.3 linkuse as main transcript	c.4079_4080insGGA	p.Glu1360dup	inframe_insertion	7/7	ENST00000324001.8
PRX	NM_001411127.1 linkuse as main transcript	c.4364_4365insGGA	p.Glu1455dup	inframe_insertion	7/7
PRX	XM_017027047.2 linkuse as main transcript	c.3977_3978insGGA	p.Glu1326dup	inframe_insertion	4/4
PRX	NM_020956.2 linkuse as main transcript	c.4284_4285insGGA		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.4079_4080insGGA	p.Glu1360dup	inframe_insertion	7/7	1	NM_181882.3	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.000370

AC:

AN:

151214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.000193

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000236

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000432

AC:

AN:

145830

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

78150

show subpopulations

Gnomad AFR exome

AF:

0.000919

Gnomad AMR exome

AF:

0.000138

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.000104

Gnomad SAS exome

AF:

0.00215

Gnomad FIN exome

AF:

0.000334

Gnomad NFE exome

AF:

0.0000592

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

AF:

0.000126

AC:

183

AN:

1453796

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

722798

show subpopulations

Gnomad4 AFR exome

AF:

0.000811

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.000425

Gnomad4 EAS exome

AF:

0.0000760

Gnomad4 SAS exome

AF:

0.000715

Gnomad4 FIN exome

AF:

0.0000944

Gnomad4 NFE exome

AF:

0.0000443

Gnomad4 OTH exome

AF:

0.000350

GnomAD4 genome

AF:

0.000410

AC:

AN:

151330

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

AN XY:

73928

show subpopulations

Gnomad4 AFR

AF:

0.000798

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000832

Gnomad4 FIN

AF:

0.000193

Gnomad4 NFE

AF:

0.000236

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2019

In-frame duplication in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease type 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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