rs369072136

chr19-40394181-G-Achr19-40394181-G-C

Variant summary

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

The NM_181882.3(PRX):c.4171C>T(p.Arg1391Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,587,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1391G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.03

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=0.06813648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.4171C>T	p.Arg1391Trp	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.4456C>T	p.Arg1486Trp	missense_variant	7/7
PRX	XM_017027047.2	c.4069C>T	p.Arg1357Trp	missense_variant	4/4
PRX	NM_020956.2	c.*4376C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.4171C>T	p.Arg1391Trp	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000383 AC: 9 AN: 234688 Hom.: 0 AF XY: 0.0000551 AC XY: 7 AN XY: 126998

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.0000311

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: 0.0000374

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.0000397 AC: 57 AN: 1435390 Hom.: 0 Cov.: 30 AF XY: 0.0000493 AC XY: 35 AN XY: 710498

Gnomad4 AFR exome AF: 0.000183

Gnomad4 AMR exome AF: 0.0000237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000420

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74304

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.0000796 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2019

The p.R1391W variant (also known as c.4171C>T), located in coding exon 4 of the PRX gene, results from a C to T substitution at nucleotide position 4171. The arginine at codon 1391 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not 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

Invitae

Aug 26, 2021

This sequence change replaces arginine with tryptophan at codon 1391 of the PRX protein (p.Arg1391Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs369072136, ExAC 0.02%). 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: 476972). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	13
Dann	Benign	0.91
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.063
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0	B
Vest4		0.20
MVP		0.25
MPC		0.23
ClinPred		0.021	T
GERP RS		-2.2
Varity_R		0.076
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

Other links and lift over

dbSNP: rs369072136; hg19: chr19-40900088;