rs139950446

Positions:

chr19-40394650-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_181882.3(PRX):c.3702C>T(p.Gly1234Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,607,154 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 39 hom. )

Consequence

PRX
NM_181882.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -7.27

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]

PRX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 19-40394650-G-A is Benign according to our data. Variant chr19-40394650-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 329255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40394650-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-7.27 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00328 (499/151992) while in subpopulation EAS AF= 0.0333 (171/5138). AF 95% confidence interval is 0.0292. There are 8 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3 linkuse as main transcript	c.3702C>T	p.Gly1234Gly	synonymous_variant	7/7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 linkuse as main transcript	c.3987C>T	p.Gly1329Gly	synonymous_variant	7/7		NP_001398056.1
PRX	XM_017027047.2 linkuse as main transcript	c.3600C>T	p.Gly1200Gly	synonymous_variant	4/4		XP_016882536.1
PRX	NM_020956.2 linkuse as main transcript	c.*3907C>T		3_prime_UTR_variant	6/6		NP_066007.1	Q9BXM0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 linkuse as main transcript	c.3702C>T	p.Gly1234Gly	synonymous_variant	7/7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.00329

AC:

499

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0332

Gnomad SAS

AF:

0.00313

Gnomad FIN

AF:

0.0215

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00483

AC:

1174

AN:

243202

Hom.:

AF XY:

0.00444

AC XY:

589

AN XY:

132612

show subpopulations

Gnomad AFR exome

AF:

0.0000639

Gnomad AMR exome

AF:

0.000639

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.0300

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00515

GnomAD4 exome

AF:

0.00215

AC:

3130

AN:

1455162

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

1486

AN XY:

724210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0289

Gnomad4 SAS exome

AF:

0.00148

Gnomad4 FIN exome

AF:

0.0259

Gnomad4 NFE exome

AF:

0.000295

Gnomad4 OTH exome

AF:

0.00456

GnomAD4 genome

AF:

0.00328

AC:

499

AN:

151992

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

325

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0333

Gnomad4 SAS

AF:

0.00313

Gnomad4 FIN

AF:

0.0215

Gnomad4 NFE

AF:

0.000854

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.00130

Hom.:

Bravo

AF:

0.00170

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2016

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. -

Charcot-Marie-Tooth disease type 4F

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.093

DANN

Benign

0.58

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over