rs76756143

Positions:

chr19-40397798-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181882.3(PRX):c.554G>A(p.Arg185His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,578,880 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 5 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.27

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068308413).

BP6

Variant 19-40397798-C-T is Benign according to our data. Variant chr19-40397798-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 329284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00279 (425/152326) while in subpopulation AFR AF= 0.00962 (400/41586). AF 95% confidence interval is 0.00884. There are 2 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PRX	NM_181882.3 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1 linkuse as main transcript	c.839G>A	p.Arg280His	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2 linkuse as main transcript	c.452G>A	p.Arg151His	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2 linkuse as main transcript	c.*759G>A		3_prime_UTR_variant	6/6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	7/7	1	NM_181882.3	ENSP00000326018	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

425

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000719

AC:

132

AN:

183578

Hom.:

AF XY:

0.000651

AC XY:

AN XY:

99778

show subpopulations

Gnomad AFR exome

AF:

0.00941

Gnomad AMR exome

AF:

0.000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000907

Gnomad SAS exome

AF:

0.000351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000651

Gnomad OTH exome

AF:

0.000626

GnomAD4 exome

AF:

0.000347

AC:

495

AN:

1426554

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

239

AN XY:

706190

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.000396

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000363

Gnomad4 SAS exome

AF:

0.000365

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000310

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.00279

AC:

425

AN:

152326

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

205

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00962

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000803

Hom.:

Bravo

AF:

0.00315

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00824

AC:

ESP6500EA

AF:

0.000372

AC:

ExAC

AF:

0.000830

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2019

- -

Charcot-Marie-Tooth disease type 4F

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.67

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.89

REVEL

Benign

0.032

Sift

Benign

0.11

Sift4G

Uncertain

0.020

Polyphen

0.022

Vest4

0.15

MVP

0.36

MPC

0.71

ClinPred

0.026

GERP RS

3.7

Varity_R

0.071

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over