rs146222815

Positions:

• chr19-40395143-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181882.3(PRX):​c.3209G>A​(p.Arg1070Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.352

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]

ACMG classification

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=0.14971825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.3209G>A	p.Arg1070Gln	missense_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.3494G>A	p.Arg1165Gln	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2	c.3107G>A	p.Arg1036Gln	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2	c.*3414G>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	c.3209G>A	p.Arg1070Gln	missense_variant	7/7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000309

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000318 AC: 80 AN: 251332 Hom.: 0 AF XY: 0.000353 AC XY: 48 AN XY: 135850

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000572

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000250 AC: 366 AN: 1461856 Hom.: 0 Cov.: 99 AF XY: 0.000241 AC XY: 175 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74348

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2017	A variant of uncertain significance has been identified in the PRX gene. The R1070Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1070Q 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 R1070Q 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, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 29, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 27, 2017

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2023

The c.3209G>A (p.R1070Q) alteration is located in exon 7 (coding exon 4) of the PRX gene. This alteration results from a G to A substitution at nucleotide position 3209, causing the arginine (R) at amino acid position 1070 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, 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 12, 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 type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1070 of the PRX protein (p.Arg1070Gln). This variant is present in population databases (rs146222815, gnomAD 0.05%). This missense change has been observed in individual(s) with hereditary motor neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 329260). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRX protein function. 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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.015	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.092
Sift	Benign	0.19	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.45
MVP		0.64
MPC		0.48
ClinPred		0.062	T
GERP RS		4.7
Varity_R		0.095
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs146222815; hg19: chr19-40901050;