19-40396791-GTACCTCTGGAAGCCGCACCTCCGGCACAGCCATCTCTGGCACCTTTGGGAGTTTCATCTCTGACACTTTGGGCAGCTC-GTACCTCTGGAAGCCGCACCTCCGGCACAGCCATCTCTGGCACCTTTGGGAGTTTCATCTCTGACACTTTGGGCAGCTCTACCTCTGGAAGCCGCACCTCCGGCACAGCCATCTCTGGCACCTTTGGGAGTTTCATCTCTGACACTTTGGGCAGCTC

Position:

• chr19-40396791-GTACCTCTGGAAGCCGCACCTCCGGCACAGCCATCTCTGGCACCTTTGGGAGTTTCATCTCTGACACTTTGGGCAGCTC-GTACCTCTGGAAGCCGCACCTCCGGCACAGCCATCTCTGGCACCTTTGGGAGTTTCATCTCTGACACTTTGGGCAGCTCTACCTCTGGAAGCCGCACCTCCGGCACAGCCATCTCTGGCACCTTTGGGAGTTTCATCTCTGACACTTTGGGCAGCTC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_181882.3(PRX):​c.1560_1561insGAGCTGCCCAAAGTGTCAGAGATGAAACTCCCAAAGGTGCCAGAGATGGCTGTGCCGGAGGTGCGGCTTCCAGAGGTA​(p.Glu495_Val520dup) variant causes a inframe insertion 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRX NM_181882.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.740

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_181882.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.1560_1561insGAGCTGCCCAAAGTGTCAGAGATGAAACTCCCAAAGGTGCCAGAGATGGCTGTGCCGGAGGTGCGGCTTCCAGAGGTA	p.Glu495_Val520dup	inframe_insertion	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.1845_1846insGAGCTGCCCAAAGTGTCAGAGATGAAACTCCCAAAGGTGCCAGAGATGGCTGTGCCGGAGGTGCGGCTTCCAGAGGTA	p.Glu590_Val615dup	inframe_insertion	7/7
PRX	XM_017027047.2	c.1458_1459insGAGCTGCCCAAAGTGTCAGAGATGAAACTCCCAAAGGTGCCAGAGATGGCTGTGCCGGAGGTGCGGCTTCCAGAGGTA	p.Glu461_Val486dup	inframe_insertion	4/4
PRX	NM_020956.2	c.*1765_*1766insGAGCTGCCCAAAGTGTCAGAGATGAAACTCCCAAAGGTGCCAGAGATGGCTGTGCCGGAGGTGCGGCTTCCAGAGGTA		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.1560_1561insGAGCTGCCCAAAGTGTCAGAGATGAAACTCCCAAAGGTGCCAGAGATGGCTGTGCCGGAGGTGCGGCTTCCAGAGGTA	p.Glu495_Val520dup	inframe_insertion	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 09, 2019

Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with PRX-related conditions. This variant is not present in population databases (ExAC no frequency). This variant, c.1483_1560dup, results in the insertion of 26 amino acid(s) to the PRX protein (p.Glu495_Val520dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555801137; hg19: chr19-40902698;