20-10652212-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1PP2PP3_ModerateBS1_SupportingBS2
The NM_000214.3(JAG1):āc.925G>Cā(p.Gly309Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,613,934 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G309W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000214.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.925G>C | p.Gly309Arg | missense_variant | 7/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.925G>C | p.Gly309Arg | missense_variant | 7/26 | 1 | NM_000214.3 | P1 | |
JAG1 | ENST00000423891.6 | n.791G>C | non_coding_transcript_exon_variant | 5/25 | 2 | ||||
JAG1 | ENST00000617965.2 | n.294G>C | non_coding_transcript_exon_variant | 2/17 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251392Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135872
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461794Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727214
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74318
ClinVar
Submissions by phenotype
Alagille syndrome due to a JAG1 point mutation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 30, 2023 | ClinVar contains an entry for this variant (Variation ID: 518844). This missense change has been observed in individual(s) with isolated Tetralogy of Fallot (PMID: 22040217). This variant is present in population databases (rs750195672, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 309 of the JAG1 protein (p.Gly309Arg). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt JAG1 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. - |
JAG1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 04, 2023 | The JAG1 c.925G>C variant is predicted to result in the amino acid substitution p.Gly309Arg. This variant was reported in an individual with tetralogy of Fallot (Guida et al. 2011. PubMed ID: 22040217). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-10632860-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2018 | The p.G309R variant (also known as c.925G>C), located in coding exon 7 of the JAG1 gene, results from a G to C substitution at nucleotide position 925. The glycine at codon 309 is replaced by arginine, an amino acid with dissimilar properties. In one study, this alteration was detected in an individual with tetralogy of Fallot and some dysmorphic features (Guida V et al. Clin Genet. 2011;80:591-4). This amino acid position is not well conserved in available vertebrate species, and arginine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at