rs118071705

chr19-40397621-G-Achr19-40397621-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181882.3(PRX):c.731C>T(p.Ala244Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,541,072 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A244E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (31 hom., cov: 33)
  • Exomes 𝑓: 0.018 (279 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.591

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023050308).
• BP6: Variant 19-40397621-G-A is Benign according to our data. Variant chr19-40397621-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40397621-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2065/152304) while in subpopulation NFE AF= 0.021 (1427/68004). AF 95% confidence interval is 0.0201. There are 31 homozygotes in gnomad4. There are 987 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.731C>T	p.Ala244Val	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.1016C>T	p.Ala339Val	missense_variant	7/7
PRX	XM_017027047.2	c.629C>T	p.Ala210Val	missense_variant	4/4
PRX	NM_020956.2	c.*936C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.731C>T	p.Ala244Val	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2066 AN: 152188 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0128 AC: 1753 AN: 137004 Hom.: 25 AF XY: 0.0121 AC XY: 907 AN XY: 75016

Gnomad AFR exome AF: 0.00359

Gnomad AMR exome AF: 0.00718

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.0000908

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0182 AC: 25278 AN: 1388768 Hom.: 279 Cov.: 35 AF XY: 0.0178 AC XY: 12195 AN XY: 685704

Gnomad4 AFR exome AF: 0.00267

Gnomad4 AMR exome AF: 0.00718

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.0000553

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0136 AC: 2065 AN: 152304 Hom.: 31 Cov.: 33 AF XY: 0.0133 AC XY: 987 AN XY: 74472

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0244

Gnomad4 NFE AF: 0.0210

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00990 Hom.: 5

Bravo AF: 0.0126

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00257 AC: 9

ESP6500EA AF: 0.0156 AC: 113

ExAC AF: 0.00794 AC: 855

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2015	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 4F Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.066
Sift	Benign	0.40	T
Sift4G	Uncertain	0.021	D
Polyphen		0.095	B
Vest4		0.11
MPC		0.61
ClinPred		0.0095	T
GERP RS		3.6
Varity_R		0.040
gMVP		0.37

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: rs118071705; hg19: chr19-40903528;