rs146789340

chr19-40396869-C-G

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.1483G>C(p.Glu495Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,575,062 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (128 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.113

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=0.00758934).
• BP6: Variant 19-40396869-C-G is Benign according to our data. Variant chr19-40396869-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 215545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40396869-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1493/138960) while in subpopulation NFE AF= 0.0143 (912/63802). AF 95% confidence interval is 0.0135. There are 12 homozygotes in gnomad4. There are 739 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.1483G>C	p.Glu495Gln	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.1768G>C	p.Glu590Gln	missense_variant	7/7
PRX	XM_017027047.2	c.1381G>C	p.Glu461Gln	missense_variant	4/4
PRX	NM_020956.2	c.*1688G>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.1483G>C	p.Glu495Gln	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1494 AN: 138882 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00330

Gnomad AMI AF: 0.00254

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.0116

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0165

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0121

GnomAD3 exomes AF: 0.00508 AC: 1255 AN: 247112 Hom.: 18 AF XY: 0.00515 AC XY: 688 AN XY: 133614

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00333

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00627

Gnomad OTH exome AF: 0.00824

GnomAD4 exome AF: 0.00686 AC: 9847 AN: 1436102 Hom.: 128 Cov.: 36 AF XY: 0.00717 AC XY: 5128 AN XY: 714974

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.00743

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00755

Gnomad4 FIN exome AF: 0.0177

Gnomad4 NFE exome AF: 0.00678

Gnomad4 OTH exome AF: 0.00763

GnomAD4 genome AF: 0.0107 AC: 1493 AN: 138960 Hom.: 12 Cov.: 32 AF XY: 0.0109 AC XY: 739 AN XY: 67844

Gnomad4 AFR AF: 0.00329

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.0116

Gnomad4 EAS AF: 0.000221

Gnomad4 SAS AF: 0.0134

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0120

Alfa AF: 0.0139 Hom.: 3

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0165 AC: 142

ExAC AF: 0.00283 AC: 343

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PRX: BP4, BS2 -

Charcot-Marie-Tooth disease type 4F Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 19, 2017	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.085
Dann	Benign	0.12
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.60	N
MutationTaster	Benign	0.67	D;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.020
Sift	Benign	0.41	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.070
MVP		0.22
MPC		0.22
ClinPred		0.00034	T
GERP RS		-3.1
Varity_R		0.063
gMVP		0.076

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: rs146789340; hg19: chr19-40902776; COSMIC: COSV52532169;