19-40394272-TTCCTCCTCCTCC-TTCCTCCTCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_181882.3(PRX):c.4077_4079del(p.Glu1361del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,368,446 control chromosomes in the GnomAD database, including 726 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (139 hom., cov: 32)
  • Exomes 𝑓: 0.017 (587 hom.)
• Consequence: PRX NM_181882.3 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:4 B:8
• Conservation: PhyloP100: 1.16

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 19-40394272-TTCC-T is Benign according to our data. Variant chr19-40394272-TTCC-T is described in ClinVar as [Benign]. Clinvar id is 215547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40394272-TTCC-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.4077_4079del	p.Glu1361del	inframe_deletion	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.4362_4364del	p.Glu1456del	inframe_deletion	7/7
PRX	XM_017027047.2	c.3975_3977del	p.Glu1327del	inframe_deletion	4/4
PRX	NM_020956.2	c.*4282_*4284del		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.4077_4079del	p.Glu1361del	inframe_deletion	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3222 AN: 150898 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00790

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.0217

GnomAD3 exomes AF: 0.0729 AC: 10638 AN: 145830 Hom.: 411 AF XY: 0.0651 AC XY: 5090 AN XY: 78150

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.0149

Gnomad SAS exome AF: 0.0555

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0639

GnomAD4 exome AF: 0.0173 AC: 21017 AN: 1217436 Hom.: 587 AF XY: 0.0175 AC XY: 10444 AN XY: 596600

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00356

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.00842

Gnomad4 NFE exome AF: 0.00872

Gnomad4 OTH exome AF: 0.0191

GnomAD4 genome AF: 0.0214 AC: 3231 AN: 151010 Hom.: 139 Cov.: 32 AF XY: 0.0230 AC XY: 1698 AN XY: 73744

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00811

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.0215

Bravo AF: 0.0340

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -

Charcot-Marie-Tooth disease type 4 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -

Charcot-Marie-Tooth disease type 5 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

- -

Charcot-Marie-Tooth disease, type I Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

- -

Spinocerebellar ataxia 46 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs139624657; hg19: chr19-40900179;