17-41754957-T-C

Variant names:

• chr17-41754957-T-C
• rs551870163
• NM_002230.4:c.*787A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002230.4(JUP):​c.*787A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 203,042 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: JUP NM_002230.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -2.56
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• inherited epidermolysis bullosa

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Naxos disease

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.*787A>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.*787A>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_002230.4	ENSP00000377508.3
JUP	ENST00000310706.9	c.*490A>G		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000311113.5
JUP	ENST00000393930.5	c.*490A>G		3_prime_UTR_variant	Exon 15 of 15	5		ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000964 AC: 49 AN: 50844 Hom.: 1 Cov.: 0 AF XY: 0.00102 AC XY: 26 AN XY: 25434

African (AFR) AF: 0.00 AC: 0 AN: 1990

American (AMR) AF: 0.00 AC: 0 AN: 1462

Ashkenazi Jewish (ASJ) AF: 0.000462 AC: 1 AN: 2164

East Asian (EAS) AF: 0.00 AC: 0 AN: 4314

South Asian (SAS) AF: 0.00 AC: 0 AN: 428

European-Finnish (FIN) AF: 0.0159 AC: 46 AN: 2900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 33798

Other (OTH) AF: 0.000571 AC: 2 AN: 3504

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74410

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0157 AC: 167 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67998

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.0000529

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Naxos disease Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Arrhythmogenic right ventricular dysplasia 12 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.32
DANN	Benign	0.58
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs551870163; hg19: chr17-39911209;