rs76756143

Positions:

• chr19-40397798-C-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.554G>A​(p.Arg185His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,578,880 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. R185C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.27

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=0.0068308413).
• BP6: Variant 19-40397798-C-T is Benign according to our data. Variant chr19-40397798-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 329284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00279 (425/152326) while in subpopulation AFR AF= 0.00962 (400/41586). AF 95% confidence interval is 0.00884. There are 2 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 33. 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	UniProt
PRX	NM_181882.3	c.554G>A	p.Arg185His	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.839G>A	p.Arg280His	missense_variant	7/7
PRX	XM_017027047.2	c.452G>A	p.Arg151His	missense_variant	4/4
PRX	NM_020956.2	c.*759G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.554G>A	p.Arg185His	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 425 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000719 AC: 132 AN: 183578 Hom.: 1 AF XY: 0.000651 AC XY: 65 AN XY: 99778

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000907

Gnomad SAS exome AF: 0.000351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000651

Gnomad OTH exome AF: 0.000626

GnomAD4 exome AF: 0.000347 AC: 495 AN: 1426554 Hom.: 5 Cov.: 35 AF XY: 0.000338 AC XY: 239 AN XY: 706190

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.000396

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000363

Gnomad4 SAS exome AF: 0.000365

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000310

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00275 AC XY: 205 AN XY: 74488

Gnomad4 AFR AF: 0.00962

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000803 Hom.: 0

Bravo AF: 0.00315

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00824 AC: 34

ESP6500EA AF: 0.000372 AC: 3

ExAC AF: 0.000830 AC: 98

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Benign:1

Likely 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 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

clinical testing

GeneDx

May 14, 2019

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.67	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.032
Sift	Benign	0.11	T
Sift4G	Uncertain	0.020	D
Polyphen		0.022	B
Vest4		0.15
MVP		0.36
MPC		0.71
ClinPred		0.026	T
GERP RS		3.7
Varity_R		0.071
gMVP		0.36

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

Other links and lift over

dbSNP: rs76756143; hg19: chr19-40903705; COSMIC: COSV99397448;