rs574861276

Variant names:

• chr19-40396962-G-A
• rs574861276
• NM_181882.3:c.1390C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-40396962-G-A
• chr19-40396962-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_181882.3(PRX):​c.1390C>T​(p.Arg464*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PRX NM_181882.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.58
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 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 57 pathogenic variants in the truncated region.
• PP5: Variant 19-40396962-G-A is Pathogenic according to our data. Variant chr19-40396962-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 580375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3	c.1390C>T	p.Arg464*	stop_gained	Exon 7 of 7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.1675C>T	p.Arg559*	stop_gained	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2	c.1288C>T	p.Arg430*	stop_gained	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2	c.*1595C>T		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.1390C>T	p.Arg464*	stop_gained	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00000399 AC: 1 AN: 250720 AF XY: 0.00

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461844 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74440

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 20, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRX c.1390C>T; p.Arg464Ter variant (rs574861276) is reported in the literature in three individuals affected with Charcot-Marie-Tooth disease (Dohrn 2017, Vill 2017, Sun 2017). This variant is reported as pathogenic in ClinVar (Variation ID: 580375). At ARUP, this variant was detected in trans with another PRX variant c.1043dupG; p.Glu349fs in two siblings affected with CMT type 4F and Dejerine-Sottas disease. This variant induces an early termination codon and is predicted to result in a truncated protein. Based on available information, this variant is considered to be pathogenic. References: Dohrn et al. Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies. J Neurochem. 2017 Dec;143(5):507-522. Vill et al. Jumping Mechanography as a Complementary Testing Tool for Motor Function in Children with Hereditary Motor and Sensory Neuropathy. Neuropediatrics. 2017 Dec;48(6):420-425. Sun et al. Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients. J Peripher Nerv Syst. 2017 Mar;22(1):13-18. -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Apr 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the PRX gene (p.Arg464*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 998 amino acids of the PRX protein. For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Cys715*) that lies downstream of this variant has been determined to be pathogenic (PMID: 12112076). This suggests that deletion of this region of the PRX protein is causative of disease. This variant has been reported in an individual affected with Charcot-Marie-Tooth disease, type 4F (PMID: 27862672). This variant is present in population databases (rs574861276, ExAC 0.01%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.088	N
PhyloP100		1.6
Vest4		0.67
GERP RS		4.0
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs574861276; hg19: chr19-40902869; COSMIC: COSV52528280;