rs4803335

Positions:

• chr19-40397881-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181882.3(PRX):​c.471G>A​(p.Glu157Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,610,576 control chromosomes in the GnomAD database, including 1,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (128 hom., cov: 33)
  • Exomes 𝑓: 0.011 (1081 hom.)
• Consequence: PRX NM_181882.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-40397881-C-T is Benign according to our data. Variant chr19-40397881-C-T is described in ClinVar as [Benign]. Clinvar id is 329288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40397881-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.471G>A	p.Glu157Glu	synonymous_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.756G>A	p.Glu252Glu	synonymous_variant	7/7		NP_001398056.1
PRX	XM_017027047.2	c.369G>A	p.Glu123Glu	synonymous_variant	4/4		XP_016882536.1
PRX	NM_020956.2	c.*676G>A		3_prime_UTR_variant	6/6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.471G>A	p.Glu157Glu	synonymous_variant	7/7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2321 AN: 152220 Hom.: 126 Cov.: 33

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0337 AC: 8100 AN: 240040 Hom.: 858 AF XY: 0.0264 AC XY: 3450 AN XY: 130828

Gnomad AFR exome AF: 0.00374

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00875

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0107 AC: 15627 AN: 1458238 Hom.: 1081 Cov.: 35 AF XY: 0.00997 AC XY: 7230 AN XY: 725260

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00986

Gnomad4 FIN exome AF: 0.00323

Gnomad4 NFE exome AF: 0.00443

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0153 AC: 2328 AN: 152338 Hom.: 128 Cov.: 33 AF XY: 0.0171 AC XY: 1275 AN XY: 74488

Gnomad4 AFR AF: 0.00440

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00739 Hom.: 19

Bravo AF: 0.0272

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4803335; hg19: chr19-40903788;