rs1268527552

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181882.3(PRX):ā€‹c.3416A>Gā€‹(p.His1139Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,609,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.406
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.040913522).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRXNM_181882.3 linkuse as main transcriptc.3416A>G p.His1139Arg missense_variant 7/7 ENST00000324001.8 NP_870998.2
PRXNM_001411127.1 linkuse as main transcriptc.3701A>G p.His1234Arg missense_variant 7/7 NP_001398056.1
PRXXM_017027047.2 linkuse as main transcriptc.3314A>G p.His1105Arg missense_variant 4/4 XP_016882536.1
PRXNM_020956.2 linkuse as main transcriptc.*3621A>G 3_prime_UTR_variant 6/6 NP_066007.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRXENST00000324001.8 linkuse as main transcriptc.3416A>G p.His1139Arg missense_variant 7/71 NM_181882.3 ENSP00000326018 A2Q9BXM0-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152074
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00000808
AC:
2
AN:
247504
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134286
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1457048
Hom.:
0
Cov.:
33
AF XY:
0.00000276
AC XY:
2
AN XY:
724920
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152074
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74282
show subpopulations
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
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 24, 2021This sequence change replaces histidine with arginine at codon 1139 of the PRX protein (p.His1139Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PRX-related conditions. 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 arginine 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
0.059
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
2.2
DANN
Benign
0.47
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.77
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.32
T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.041
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.99
N
REVEL
Benign
0.046
Sift
Benign
0.88
T
Sift4G
Benign
0.26
T
Polyphen
0.0
B
Vest4
0.094
MutPred
0.38
Gain of methylation at H1139 (P = 0.0184);
MVP
0.26
MPC
0.49
ClinPred
0.017
T
GERP RS
2.8
Varity_R
0.048
gMVP
0.043

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.

Other links and lift over

dbSNP: rs1268527552; hg19: chr19-40900843; API