19-40394856-G-A

Position:

chr19-40394856-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181882.3(PRX):c.3496C>T(p.Pro1166Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,612,330 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: -0.455

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01178664).

BP6

Variant 19-40394856-G-A is Benign according to our data. Variant chr19-40394856-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216835.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5, Benign=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0011 (1603/1460076) while in subpopulation MID AF= 0.00468 (27/5768). AF 95% confidence interval is 0.0033. There are 3 homozygotes in gnomad4_exome. There are 805 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3 linkuse as main transcript	c.3496C>T	p.Pro1166Ser	missense_variant	7/7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 linkuse as main transcript	c.3781C>T	p.Pro1261Ser	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2 linkuse as main transcript	c.3394C>T	p.Pro1132Ser	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2 linkuse as main transcript	c.*3701C>T		3_prime_UTR_variant	6/6		NP_066007.1	Q9BXM0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.3496C>T	p.Pro1166Ser	missense_variant	7/7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000980

AC:

244

AN:

248870

Hom.:

AF XY:

0.00107

AC XY:

145

AN XY:

135032

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.000344

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00110

AC:

1603

AN:

1460076

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

805

AN XY:

726496

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.000155

Gnomad4 NFE exome

AF:

0.00129

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152254

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00140

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00131

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00121

AC:

147

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 16, 2023	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2022	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2020	The PRX c.3496C>T; p.Pro1166Ser variant (rs147826200) has been previously observed in a cohort of patients with chemotherapy-induced peripheral neuropathy (Beutler 2014). However, genetic variation in PRX has not been clearly demonstrated to be a risk factor for this particular type of acquired neuropathy. This variant is described in the ClinVar database (Variation ID: 216835) and is found in the general population with an overall allele frequency of 0.09% (265/280,240 alleles) in the Genome Aggregation Database. The proline at codon 1166 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on the available information, the clinical significance of this variant is uncertain. REFERENCE Beutler AS et al. Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy. Ann Neurol. 2014 Nov;76(5):727-37. -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 03, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 01, 2015	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2022

The p.P1166S variant (also known as c.3496C>T), located in coding exon 4 of the PRX gene, results from a C to T substitution at nucleotide position 3496. The proline at codon 1166 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 4F

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.12

DANN

Benign

0.47

DEOGEN2

Benign

0.16

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.50

M_CAP

Benign

0.0046

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

REVEL

Benign

0.014

Sift

Benign

0.25

Sift4G

Benign

0.10

Polyphen

0.0090

Vest4

0.053

MVP

0.22

MPC

0.69

ClinPred

0.17

GERP RS

0.78

Varity_R

0.061

gMVP

0.043

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