rs794729044
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS1_Supporting
The NM_002230.4(JUP):c.1130G>A(p.Arg377His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002230.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JUP | NM_002230.4 | c.1130G>A | p.Arg377His | missense_variant | 7/14 | ENST00000393931.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JUP | ENST00000393931.8 | c.1130G>A | p.Arg377His | missense_variant | 7/14 | 1 | NM_002230.4 | P1 | |
JUP | ENST00000310706.9 | c.1130G>A | p.Arg377His | missense_variant | 7/15 | 1 | P1 | ||
JUP | ENST00000393930.5 | c.1130G>A | p.Arg377His | missense_variant | 7/15 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251280Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135826
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461052Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 726830
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 17, 2020 | - - |
Arrhythmogenic right ventricular dysplasia 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 12, 2021 | This sequence change replaces arginine with histidine at codon 377 of the JUP protein (p.Arg377His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200433530, ExAC 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricularcardiomyopathy (PMID: 25765472). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg377 amino acid residue in JUP. Other variant(s) that disrupt this residue have been observed in individuals with JUP-related conditions (PMID: 25765472), which suggests that this may be a clinically significant amino acid residue. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at