19-40394272-TTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_181882.3(PRX):c.4074_4079dupGGAGGA(p.Glu1359_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 0.00000436 in 1,605,030 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PRX
NM_181882.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.16

Publications

6 publications found

Variant links:

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

PRX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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-TTCCTCC is Benign according to our data. Variant chr19-40394272-T-TTCCTCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1052678.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3 link	c.4074_4079dupGGAGGA	p.Glu1359_Glu1360dup	disruptive_inframe_insertion	Exon 7 of 7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 link	c.4359_4364dupGGAGGA	p.Glu1454_Glu1455dup	disruptive_inframe_insertion	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.3972_3977dupGGAGGA	p.Glu1325_Glu1326dup	disruptive_inframe_insertion	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.4279_4284dupGGAGGA		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1	Q9BXM0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 link	c.4074_4079dupGGAGGA	p.Glu1359_Glu1360dup	disruptive_inframe_insertion	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000137

AC:

AN:

145830

AF XY:

0.0000128

show subpopulations

Gnomad AFR exome

AF:

0.000102

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1453816

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722810

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

43920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39464

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107252

Other (OTH)

AF:

0.0000167

AC:

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73800

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41218

American (AMR)

AF:

0.00

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67716

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4

Uncertain:1

Feb 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with PRX-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant, c.4074_4079dup, results in the insertion of 2 amino acid(s) of the PRX protein (p.Glu1360_Glu1361dup), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases

Benign:1

Mar 20, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=84/16

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over