rs570878629

Positions:

chr17-41771799-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS1_Supporting

The NM_002230.4(JUP):c.56C>T(p.Thr19Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

JUP
NM_002230.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 3.12

Variant links:

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

JUP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a mutagenesis_site Reduces glycosylation. (size 0) in uniprot entity PLAK_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.21289116).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000119 (174/1461404) while in subpopulation AMR AF= 0.000246 (11/44700). AF 95% confidence interval is 0.000137. There are 0 homozygotes in gnomad4_exome. There are 93 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4 linkuse as main transcript	c.56C>T	p.Thr19Ile	missense_variant	2/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8 linkuse as main transcript	c.56C>T	p.Thr19Ile	missense_variant	2/14	1	NM_002230.4	ENSP00000377508	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

249428

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

174

AN:

1461404

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000580

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2022	The JUP c.56C>T; p.Thr19Ile variant (rs570878629) is reported in the literature in several individuals affected with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (Bhonsale 2015, den Haan 2009, Garcia-Pavia 2011, Haggerty 2017, Sanchez 2016, Tan 2010). This variant is also reported in ClinVar (Variation ID: 179756), and is found in the general population with an overall allele frequency of 0.012% (33/280798 alleles) in the Genome Aggregation Database. The threonine at codon 19 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.204). However, given the lack of functional data, the significance of this variant is uncertain at this time. References: Bhonsale A et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J. 2015 Apr 7;36(14):847-55. PMID: 25616645. den Haan AD et al. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. PMID: 20031617. Garcia-Pavia P et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011 Nov;97(21):1744-52. PMID: 21859740. Haggerty CM et al. Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. Genet Med. 2017 Nov;19(11):1245-1252. PMID: 28471438. Sanchez O et al. Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. PLoS One. 2016 Dec 8;11(12):e0167358. PMID: 27930701. Tan BY et al. Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Transl Res. 2010 Dec;3(6):663-73. PMID: 20857253. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2022	Reported in association with dilated cardiomyopathy (DCM) (Garcia-Pavia et al., 2001; Sanchez et al., 2016), and arrhythmogenic right ventricular cardiomyopathy (ARVC) (den Haan et al., 2009; Tan et al., 2010; Bhonsale et al., 2013; Sabater-Molina et al., 2013; te Riele et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27930701, 21859740, 20031617, 20857253, 23671136, 26187847, 27037756, 28471438, 31402444, 34026867, 35581137) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 19 of the JUP protein (p.Thr19Ile). This variant is present in population databases (rs570878629, gnomAD 0.03%). This missense change has been observed in individual(s) with JUP-related conditions (PMID: 20031617, 21859740, 25616645, 27930701). ClinVar contains an entry for this variant (Variation ID: 179756). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 13, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 20, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr19Ile variant in JUP has been reported in 1 adult with DCM as well as 3 relatives who had arrhythmia (2) or low ejection fraction (1)(Garcia-Pavia 2011) and 1 individ ual with ARVC (den Haan 2009). This variant has been identified in 11/63034 Euro pean and 2/10852 Latino chromosomes by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr19Ile variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, wh ile there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. -

Naxos disease

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. -

Arrhythmogenic right ventricular dysplasia 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The JUP c.56C>T (p.Thr19Ile) variant has been reported in two studies and is found in a heterozygous state in one individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one individual with dilated cardiomyopathy (DCM) (den Haan et al. 2009; Garcia-Pavia et al. 2011). The father of the proband with DCM was presumed to carry the variant, but had died of sudden cardiac death at age 53 and was not tested (Garcia-Pavia et al. 2011). The variant was also found in four unaffected relatives of the proband with DCM, with three showing other cardiovascular abnormalities including coronary artery disease, palpitations, and atrial fibrillation (Garcia-Pavia et al. 2011). The p.Thr19Ile variant was absent from 800 control chromosomes (den Haan et al. 2009; Garcia-Pavia et al. 2011), but is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Thr19Ile variant is classified as a variant of unknown significance, but suspicious for pathogenicity for arrhythmogenic right ventricular cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Loeys Lab, Universiteit Antwerpen

Feb 26, 2021

This sequence change results in a missense variant in the JUP gene ( p.cThr19Ile)). This variant is present in population databases with a prevalence of 33/280798in GnomAD (BS1). This variant has been reported in the literature. It was found in different individuals with ARVC and co-seggregated with disease in a family with DCM and arrhythmia (Garcia-Pavia 2011; den Haan 2009; PP1). The variant has been identified in a case of SCD with DCM and additional cardiac variants (Haggerty CM et al, 2017; BP5). No functional data are available. Prediction programs show conflicting results ( Align GVGD C0; Polyphen-2-HumDiv possibly damaging; Polyphen-2-HumVar possivley damaging; SIFT: tolerated; MutationTaster: disease causing). In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (criteria for benign and pathogenic are contradictory: BS1, PP1; BP5). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2022

This alteration is classified as 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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D;D;.;T;.;T;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.55

.;.;T;T;T;T;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.3

M;M;M;.;.;.;.;.;.

MutationTaster

Benign

0.92

D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.7

D;D;D;D;D;D;D;.;D

REVEL

Benign

0.20

Sift

Uncertain

0.0070

D;D;D;D;D;D;D;.;D

Sift4G

Uncertain

0.027

D;D;D;.;.;.;.;D;.

Polyphen

0.90

P;P;P;.;.;.;.;.;.

Vest4

0.70

MVP

0.72

MPC

0.12

ClinPred

0.27

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.093

gMVP

0.67

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