19-40394958-C-T

Position:

chr19-40394958-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181882.3(PRX):c.3394G>A(p.Gly1132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,608,036 control chromosomes in the GnomAD database, including 716,680 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1132G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.96 ( 69595 hom., cov: 32)

Exomes 𝑓: 0.94 ( 647085 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.347

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=9.3784814E-7).

BP6

Variant 19-40394958-C-T is Benign according to our data. Variant chr19-40394958-C-T is described in ClinVar as [Benign]. Clinvar id is 130053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40394958-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRX	NM_181882.3 linkuse as main transcript	c.3394G>A	p.Gly1132Arg	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1 linkuse as main transcript	c.3679G>A	p.Gly1227Arg	missense_variant	7/7
PRX	XM_017027047.2 linkuse as main transcript	c.3292G>A	p.Gly1098Arg	missense_variant	4/4
PRX	NM_020956.2 linkuse as main transcript	c.*3599G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.3394G>A	p.Gly1132Arg	missense_variant	7/7	1	NM_181882.3	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.956

AC:

145384

AN:

152112

Hom.:

69535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.989

Gnomad AMI

AF:

0.866

Gnomad AMR

AF:

0.956

Gnomad ASJ

AF:

0.954

Gnomad EAS

AF:

0.978

Gnomad SAS

AF:

0.925

Gnomad FIN

AF:

0.943

Gnomad MID

AF:

0.892

Gnomad NFE

AF:

0.940

Gnomad OTH

AF:

0.943

GnomAD3 exomes

AF:

0.946

AC:

234284

AN:

247592

Hom.:

110926

AF XY:

0.943

AC XY:

126604

AN XY:

134300

show subpopulations

Gnomad AFR exome

AF:

0.991

Gnomad AMR exome

AF:

0.955

Gnomad ASJ exome

AF:

0.944

Gnomad EAS exome

AF:

0.979

Gnomad SAS exome

AF:

0.920

Gnomad FIN exome

AF:

0.941

Gnomad NFE exome

AF:

0.940

Gnomad OTH exome

AF:

0.938

GnomAD4 exome

AF:

0.943

AC:

1372357

AN:

1455806

Hom.:

647085

Cov.:

AF XY:

0.941

AC XY:

681552

AN XY:

724130

show subpopulations

Gnomad4 AFR exome

AF:

0.991

Gnomad4 AMR exome

AF:

0.955

Gnomad4 ASJ exome

AF:

0.946

Gnomad4 EAS exome

AF:

0.981

Gnomad4 SAS exome

AF:

0.918

Gnomad4 FIN exome

AF:

0.942

Gnomad4 NFE exome

AF:

0.941

Gnomad4 OTH exome

AF:

0.946

GnomAD4 genome

AF:

0.956

AC:

145502

AN:

152230

Hom.:

69595

Cov.:

AF XY:

0.956

AC XY:

71110

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.989

Gnomad4 AMR

AF:

0.956

Gnomad4 ASJ

AF:

0.954

Gnomad4 EAS

AF:

0.978

Gnomad4 SAS

AF:

0.925

Gnomad4 FIN

AF:

0.943

Gnomad4 NFE

AF:

0.940

Gnomad4 OTH

AF:

0.944

Alfa

AF:

0.943

Hom.:

109248

Bravo

AF:

0.958

TwinsUK

AF:

0.944

AC:

3499

ALSPAC

AF:

0.949

AC:

3656

ESP6500AA

AF:

0.989

AC:

4358

ESP6500EA

AF:

0.936

AC:

8047

ExAC

AF:

0.947

AC:

114939

Asia WGS

AF:

0.956

AC:

3325

AN:

3478

EpiCase

AF:

0.926

EpiControl

AF:

0.932

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Charcot-Marie-Tooth disease type 4F

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Dejerine-Sottas disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.6

DANN

Benign

0.69

DEOGEN2

Benign

0.076

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0081

LIST_S2

Benign

0.35

MetaRNN

Benign

9.4e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.63

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

0.79

REVEL

Benign

0.036

Sift

Benign

0.13

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.018

MutPred

0.43

Gain of solvent accessibility (P = 0.0097);

MPC

0.27

ClinPred

0.0036

GERP RS

3.6

Varity_R

0.050

gMVP

0.078

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