rs759435622

chr19-40394051-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.4301G>A(p.Arg1434Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,600 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1434W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.151

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=0.164568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.4301G>A	p.Arg1434Gln	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.4586G>A	p.Arg1529Gln	missense_variant	7/7
PRX	XM_017027047.2	c.4199G>A	p.Arg1400Gln	missense_variant	4/4
PRX	NM_020956.2	c.*4506G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.4301G>A	p.Arg1434Gln	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000439 AC: 11 AN: 250524 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460406 Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 726264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1434 of the PRX protein (p.Arg1434Gln). This variant is present in population databases (rs759435622, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 543420). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	-0.51	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.068
Sift	Benign	0.18	T
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.41		Loss of methylation at R1434 (P = 0.0659);
MVP		0.42
MPC		0.26
ClinPred		0.18	T
GERP RS		3.8
Varity_R		0.042
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759435622; hg19: chr19-40899958; COSMIC: COSV52521383; COSMIC: COSV52521383;