19-40396515-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.1837G>A(p.Val613Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,902 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.878

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=0.1279231).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.1837G>A	p.Val613Met	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.2122G>A	p.Val708Met	missense_variant	7/7
PRX	XM_017027047.2	c.1735G>A	p.Val579Met	missense_variant	4/4
PRX	NM_020956.2	c.*2042G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.1837G>A	p.Val613Met	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 250942 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

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: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461776 Hom.: 0 Cov.: 37 AF XY: 0.0000399 AC XY: 29 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

Gnomad4 AFR AF: 0.00

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: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 01, 2023

BP4 -

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 613 of the PRX protein (p.Val613Met). This variant is present in population databases (rs773222045, gnomAD 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: 216833). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.044
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.066
Sift	Benign	0.26	T
Sift4G	Benign	0.10	T
Polyphen		0.98	D
Vest4		0.19
MVP		0.36
MPC		0.68
ClinPred		0.11	T
GERP RS		3.4
Varity_R		0.053
gMVP		0.073

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: rs773222045; hg19: chr19-40902422;