19-40394550-C-G

Position:

chr19-40394550-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181882.3(PRX):c.3802G>C(p.Ala1268Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000607 in 1,606,650 control chromosomes in the GnomAD database, including 6 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 4 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.136

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037314594).

BP6

Variant 19-40394550-C-G is Benign according to our data. Variant chr19-40394550-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382637.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00311 (474/152270) while in subpopulation AFR AF= 0.0108 (448/41540). AF 95% confidence interval is 0.00996. There are 2 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PRX	NM_181882.3 linkuse as main transcript	c.3802G>C	p.Ala1268Pro	missense_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1 linkuse as main transcript	c.4087G>C	p.Ala1363Pro	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2 linkuse as main transcript	c.3700G>C	p.Ala1234Pro	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2 linkuse as main transcript	c.*4007G>C		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 linkuse as main transcript	c.3802G>C	p.Ala1268Pro	missense_variant	7/7	1	NM_181882.3	ENSP00000326018	A2	Q9BXM0-1

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

468

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000441

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000820

AC:

192

AN:

234008

Hom.:

AF XY:

0.000579

AC XY:

AN XY:

127884

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.000598

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000338

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000954

Gnomad OTH exome

AF:

0.000690

GnomAD4 exome

AF:

0.000345

AC:

502

AN:

1454380

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

206

AN XY:

723404

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.000592

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000468

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000948

GnomAD4 genome

AF:

0.00311

AC:

474

AN:

152270

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0108

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.000228

Hom.:

Bravo

AF:

0.00355

ESP6500AA

AF:

0.00639

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000859

AC:

104

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4F

Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2020

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

1.4

REVEL

Benign

0.053

Sift

Benign

0.35

Sift4G

Benign

0.11

Polyphen

0.73

Vest4

0.14

MVP

0.45

MPC

0.30

ClinPred

0.0033

GERP RS

2.6

Varity_R

0.048

gMVP

0.11

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