19-40394272-TTCCTCCTCCTCC-TTCCTCCTCCTCCTCC

Variant names:

• chr19-40394272-T-TTCC
• rs139624657
• NM_181882.3:c.4077_4079dupGGA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_181882.3(PRX):​c.4077_4079dupGGA​(p.Glu1360dup) variant causes a disruptive 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 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.16
• Publications: 6 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), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_181882.3
• 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 VariationId is 699561.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	NM_181882.3	MANE Select	c.4077_4079dupGGA	p.Glu1360dup	disruptive_inframe_insertion	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.4362_4364dupGGA	p.Glu1455dup	disruptive_inframe_insertion	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*4282_*4284dupGGA		3_prime_UTR	Exon 6 of 6	NP_066007.1	Q9BXM0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	ENST00000324001.8	TSL:1 MANE Select	c.4077_4079dupGGA	p.Glu1360dup	disruptive_inframe_insertion	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*4282_*4284dupGGA		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.4362_4364dupGGA	p.Glu1455dup	disruptive_inframe_insertion	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.000370 AC: 56 AN: 151214 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000432 AC: 63 AN: 145830 AF XY: 0.000397

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 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.: 0 Cov.: 29 AF XY: 0.000123 AC XY: 89 AN XY: 722798

African (AFR) AF: 0.000811 AC: 27 AN: 33292

American (AMR) AF: 0.000137 AC: 6 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.000425 AC: 11 AN: 25896

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39464

South Asian (SAS) AF: 0.000715 AC: 61 AN: 85280

European-Finnish (FIN) AF: 0.0000944 AC: 5 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000443 AC: 49 AN: 1107236

Other (OTH) AF: 0.000350 AC: 21 AN: 60000

GnomAD4 genome AF: 0.000410 AC: 62 AN: 151330 Hom.: 0 Cov.: 32 AF XY: 0.000338 AC XY: 25 AN XY: 73928

African (AFR) AF: 0.000798 AC: 33 AN: 41340

American (AMR) AF: 0.000328 AC: 5 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5122

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4806

European-Finnish (FIN) AF: 0.000193 AC: 2 AN: 10346

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

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67708

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.000518 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs139624657; hg19: chr19-40900179;