rs1555800610

chr19-40394995-ACTGACGGCCACAGCCCCCTCTGCCCTCCCTTCCTCCTGGGCGCCCAGCGTGACCAGCTCCACCTCGGGGAT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_181882.3(PRX):c.3286_3356del(p.Ile1096TrpfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000933 in 1,608,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I1096I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PRX
NM_181882.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.888

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 Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-40394995-ACTGACGGCCACAGCCCCCTCTGCCCTCCCTTCCTCCTGGGCGCCCAGCGTGACCAGCTCCACCTCGGGGAT-A is Pathogenic according to our data. Variant chr19-40394995-ACTGACGGCCACAGCCCCCTCTGCCCTCCCTTCCTCCTGGGCGCCCAGCGTGACCAGCTCCACCTCGGGGAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRX	NM_181882.3 linkuse as main transcript	c.3286_3356del	p.Ile1096TrpfsTer18	frameshift_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1 linkuse as main transcript	c.3571_3641del	p.Ile1191TrpfsTer18	frameshift_variant	7/7
PRX	XM_017027047.2 linkuse as main transcript	c.3184_3254del	p.Ile1062TrpfsTer18	frameshift_variant	4/4
PRX	NM_020956.2 linkuse as main transcript	c.3491_3561del		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.3286_3356del	p.Ile1096TrpfsTer18	frameshift_variant	7/7	1	NM_181882.3	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151434

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247424

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000961

AC:

AN:

1456874

Hom.:

AF XY:

0.00000690

AC XY:

AN XY:

724978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151434

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73896

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 13, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2023	Frameshift variant predicted to result in protein truncation, as the last 366 amino acids are replaced with 17 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32376792, 32460404, 18410371) -

Charcot-Marie-Tooth disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2022

ClinVar contains an entry for this variant (Variation ID: 448139). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 18410371, 32460404). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ile1096Trpfs*18) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 366 amino acid(s) of the PRX protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRX protein in which other variant(s) (p.Gln1169*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

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