rs281865061

Positions:

• chr19-40398753-AG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_181882.3(PRX):​c.247delC​(p.Leu83fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRX NM_181882.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1 O:1
• Conservation: PhyloP100: 1.84

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.247delC	p.Leu83fs	frameshift_variant	6/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.532delC	p.Leu178fs	frameshift_variant	6/7		NP_001398056.1
PRX	NM_020956.2	c.247delC	p.Leu83fs	frameshift_variant	6/6		NP_066007.1
PRX	XM_017027047.2	c.145delC	p.Leu49fs	frameshift_variant	3/4		XP_016882536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.247delC	p.Leu83fs	frameshift_variant	6/7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive Dejerine-Sottas syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2002

- -

Dejerine-Sottas disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Charcot-Marie-Tooth disease type 4F Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs281865061; hg19: chr19-40904660;