chr19-40394240-C-T

Position:

chr19-40394240-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181882.3(PRX):c.4112G>A(p.Arg1371Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000492 in 1,605,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.111

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17371452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3 linkuse as main transcript	c.4112G>A	p.Arg1371Gln	missense_variant	7/7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 linkuse as main transcript	c.4397G>A	p.Arg1466Gln	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2 linkuse as main transcript	c.4010G>A	p.Arg1337Gln	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2 linkuse as main transcript	c.*4317G>A		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.4112G>A	p.Arg1371Gln	missense_variant	7/7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

244476

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132778

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000482

AC:

AN:

1453356

Hom.:

Cov.:

AF XY:

0.0000499

AC XY:

AN XY:

721498

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000752

Gnomad4 NFE exome

AF:

0.0000506

Gnomad4 OTH exome

AF:

0.0000667

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PRX p.Arg1371Gln variant was not identified in the literature but was identified in dbSNP (ID: rs377009047), ClinVar (classified as uncertain significance by Invitae and GeneDx), and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 6 of 275768 chromosomes at a frequency of 0.00002176 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 2 of 23996 chromosomes (freq: 0.000083) and European (non-Finnish) in 4 of 125214 chromosomes (freq: 0.000032), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Arg1371 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2016	The R1371Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1371Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R1371Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, Glutamine is observed at this position in evolution. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2020

The p.R1371Q variant (also known as c.4112G>A), located in coding exon 4 of the PRX gene, results from a G to A substitution at nucleotide position 4112. The arginine at codon 1371 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available 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 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces arginine with glutamine at codon 1371 of the PRX protein (p.Arg1371Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs377009047, ExAC 0.005%). This variant has not been reported in the literature in individuals affected with PRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 246575). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.78

M_CAP

Benign

0.015

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.97

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.97

REVEL

Benign

0.065

Sift

Benign

0.21

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.17

MVP

0.47

MPC

0.48

ClinPred

0.11

GERP RS

2.7

Varity_R

0.050

gMVP

0.49

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