rs376051686
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1
The NM_002230.4(JUP):c.1507G>A(p.Gly503Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,606,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G503G) has been classified as Likely benign.
Frequency
Consequence
NM_002230.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JUP | NM_002230.4 | c.1507G>A | p.Gly503Ser | missense_variant | 9/14 | ENST00000393931.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JUP | ENST00000393931.8 | c.1507G>A | p.Gly503Ser | missense_variant | 9/14 | 1 | NM_002230.4 | P1 | |
JUP | ENST00000310706.9 | c.1507G>A | p.Gly503Ser | missense_variant | 9/15 | 1 | P1 | ||
JUP | ENST00000393930.5 | c.1507G>A | p.Gly503Ser | missense_variant | 9/15 | 5 | P1 | ||
JUP | ENST00000585793.1 | n.105G>A | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000224 AC: 34AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000929 AC: 23AN: 247534Hom.: 0 AF XY: 0.000112 AC XY: 15AN XY: 133988
GnomAD4 exome AF: 0.0000378 AC: 55AN: 1454248Hom.: 0 Cov.: 32 AF XY: 0.0000554 AC XY: 40AN XY: 721928
GnomAD4 genome ? AF: 0.000223 AC: 34AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74432
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Left ventricular noncompaction Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 26, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 08, 2023 | Variant summary: JUP c.1507G>A (p.Gly503Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 247534 control chromosomes. The observed variant frequency is approximately 14.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1507G>A in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as VUS while two classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2022 | 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. - |
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at