20-10672701-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000214.3(JAG1):c.387G>A(p.Pro129Pro) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000214.3 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.387G>A | p.Pro129Pro | splice_region_variant, synonymous_variant | Exon 2 of 26 | 1 | NM_000214.3 | ENSP00000254958.4 | ||
ENSG00000270792 | ENST00000667822.1 | n.7C>T | non_coding_transcript_exon_variant | Exon 1 of 2 | ||||||
ENSG00000270792 | ENST00000605292.5 | n.-227C>T | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000122 AC: 3AN: 246644Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134382
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460216Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726484
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Alagille syndrome due to a JAG1 point mutation Uncertain:1
This sequence change affects codon 129 of the JAG1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the JAG1 protein. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs766008628, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with JAG1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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