rs1555828321
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000214.3(JAG1):c.1899_1900del(p.Cys633Ter) variant causes a stop gained, frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
JAG1
NM_000214.3 stop_gained, frameshift
NM_000214.3 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
JAG1 (HGNC:6188): (jagged canonical Notch ligand 1) The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human jagged 1 is the ligand for the receptor notch 1, the latter is involved in signaling processes. Mutations that alter the jagged 1 protein cause Alagille syndrome. Jagged 1 signalling through notch 1 has also been shown to play a role in hematopoiesis. [provided by RefSeq, Nov 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-10646069-TCA-T is Pathogenic according to our data. Variant chr20-10646069-TCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 500252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10646069-TCA-T is described in Lovd as [Pathogenic]. Variant chr20-10646069-TCA-T is described in Lovd as [Pathogenic]. Variant chr20-10646069-TCA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.1899_1900del | p.Cys633Ter | stop_gained, frameshift_variant | 15/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.1899_1900del | p.Cys633Ter | stop_gained, frameshift_variant | 15/26 | 1 | NM_000214.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alagille syndrome due to a JAG1 point mutation Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2022 | ClinVar contains an entry for this variant (Variation ID: 500252). This premature translational stop signal has been observed in individual(s) with Alagille syndrome (PMID: 10220506, 34185059). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys633*) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26076142, 31343788, 10220506) - |
Computational scores
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Calibrated prediction
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at