rs149715830

chr19-40396778-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_181882.3(PRX):c.1574T>C(p.Val525Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,608,936 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (2 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: 0.743

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01118499).
• BP6: Variant 19-40396778-A-G is Benign according to our data. Variant chr19-40396778-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242179.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=4, Benign=1}. Variant chr19-40396778-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.1574T>C	p.Val525Ala	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.1859T>C	p.Val620Ala	missense_variant	7/7
PRX	XM_017027047.2	c.1472T>C	p.Val491Ala	missense_variant	4/4
PRX	NM_020956.2	c.*1779T>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.1574T>C	p.Val525Ala	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 151838 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00252

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000570 AC: 143 AN: 250708 Hom.: 0 AF XY: 0.000560 AC XY: 76 AN XY: 135612

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000772 AC: 1125 AN: 1456982 Hom.: 2 Cov.: 36 AF XY: 0.000851 AC XY: 617 AN XY: 724740

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.000422

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.000944

Gnomad4 OTH exome AF: 0.000581

GnomAD4 genome AF: 0.00128 AC: 195 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74292

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000473

Gnomad4 NFE AF: 0.00252

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00120 AC: 146

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2023	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PRX: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PRX p.Val525Ala variant was identified in 3 of 950 proband chromosomes (frequency: 0.0032) from individuals or families with Inherited Peripheral Neuropathies and was not identified in 4492 control chromosomes from healthy individuals (Schabhüttl_2014_PMID: 24627108; Antoniadi_2015_PMID: 26392352). The variant was also identified in dbSNP (ID: rs149715830) and in ClinVar where there are conflicting interpretations of pathogenicity for Charcot-Marie-Tooth disease type 4 from five submitters: 4x uncertain significance (Invitae, Illumina Clinical Services Laboratory, EGL Genetic Diagnostics, and Praxis fuer Humangenetik Tuebingen) and 1x likely benign by GeneDx. The variant was identified in control databases in 193 of 282028 chromosomes at a frequency of 0.000684 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 160 of 128602 chromosomes (freq: 0.001244), Other in 7 of 7216 chromosomes (freq: 0.00097), European (Finnish) in 12 of 25114 chromosomes (freq: 0.000478), African in 8 of 24778 chromosomes (freq: 0.000323), Ashkenazi Jewish in 2 of 10336 chromosomes (freq: 0.000194), Latino in 3 of 35432 chromosomes (freq: 0.000085) and South Asian in 1 of 30616 chromosomes (freq: 0.000033); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Val525 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 24627108, 26392352, 32376792) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2024	Variant summary: PRX c.1574T>C (p.Val525Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 250708 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database. c.1574T>C has been reported in the literature in several individuals affected with Inherited peripheral neuropathies or undertaking neuroinflammation/CMT panel testing, without strong evidence for causality (example, McCreary_2019, Schabhuttl_2014, Volodarsky_2021). These report(s) do not provide unequivocal conclusions about association of the variant with PRX-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31664448, 24627108, 32376792). ClinVar contains an entry for this variant (Variation ID: 242179). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 24, 2020	- -

Charcot-Marie-Tooth disease Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -

Charcot-Marie-Tooth disease type 4F Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 525 of the PRX protein (p.Val525Ala). This variant is present in population databases (rs149715830, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PRX-related conditions (PMID: 24627108, 26392352, 32376792). ClinVar contains an entry for this variant (Variation ID: 242179). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	9.4
Dann	Benign	0.17
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.063
Sift	Benign	0.61	T
Sift4G	Benign	0.78	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.23
MPC		0.42
ClinPred		0.0086	T
GERP RS		3.9
Varity_R		0.050
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

Other links and lift over

dbSNP: rs149715830; hg19: chr19-40902685;