dbSNP rs200033507: PRX:p.Leu275Ile (chr19-40397529-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181882.3(PRX):c.823C>A(p.Leu275Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,544,562 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L275L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:7O:1

Conservation

PhyloP100: -0.179

Publications

4 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), Ambry Genetics, Orphanet
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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016151339).

BP6

Variant 19-40397529-G-T is Benign according to our data. Variant chr19-40397529-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216836.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00105 (160/152352) while in subpopulation NFE AF = 0.00213 (145/68020). AF 95% confidence interval is 0.00185. There are 1 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRX	NM_181882.3	MANE Select	c.823C>A	p.Leu275Ile	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1		c.1108C>A	p.Leu370Ile	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
PRX	NM_020956.2		c.*1028C>A		3_prime_UTR	Exon 6 of 6	NP_066007.1	Q9BXM0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRX	ENST00000324001.8	TSL:1 MANE Select	c.823C>A	p.Leu275Ile	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
PRX	ENST00000291825.11	TSL:1	c.*1028C>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
PRX	ENST00000674005.2		c.1108C>A	p.Leu370Ile	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00213

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000935

AC:

133

AN:

142232

AF XY:

0.000875

show subpopulations

Gnomad AFR exome

AF:

0.000299

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000284

Gnomad NFE exome

AF:

0.00225

Gnomad OTH exome

AF:

0.000723

GnomAD4 exome

AF:

0.00179

AC:

2490

AN:

1392210

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1155

AN XY:

686700

show subpopulations

African (AFR)

AF:

0.000189

AC:

AN:

31672

American (AMR)

AF:

0.0000836

AC:

AN:

35892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25068

East Asian (EAS)

AF:

0.00

AC:

AN:

35888

South Asian (SAS)

AF:

0.00

AC:

AN:

79822

European-Finnish (FIN)

AF:

0.000261

AC:

AN:

42174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.00225

AC:

2423

AN:

1078608

Other (OTH)

AF:

0.000813

AC:

AN:

57836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

178

356

533

711

889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.00105

AC:

160

AN:

152352

Hom.:

Cov.:

AF XY:

0.000939

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000288

AC:

AN:

41596

American (AMR)

AF:

0.000196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00213

AC:

145

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000276

AC:

ESP6500EA

AF:

0.000928

AC:

ExAC

AF:

0.000497

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

Charcot-Marie-Tooth disease type 4F (2)

Inborn genetic diseases (1)

PRX-related disorder (1)

Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.70

M_CAP

Benign

0.021

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.14

PhyloP100

-0.18

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.13

REVEL

Benign

0.052

Sift

Benign

0.54

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.18

MVP

0.41

MPC

0.55

ClinPred

0.033

GERP RS

1.2

Varity_R

0.053

gMVP

0.087

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over