rs1437309558
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000214.3(JAG1):c.2473C>T(p.Gln825Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
JAG1
NM_000214.3 stop_gained
NM_000214.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 10.0
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 12 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 20-10642587-G-A is Pathogenic according to our data. Variant chr20-10642587-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 536533.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-10642587-G-A is described in Lovd as [Pathogenic]. Variant chr20-10642587-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.2473C>T | p.Gln825Ter | stop_gained | 21/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.2473C>T | p.Gln825Ter | stop_gained | 21/26 | 1 | NM_000214.3 | P1 | |
JAG1 | ENST00000423891.6 | n.2339C>T | non_coding_transcript_exon_variant | 19/25 | 2 | ||||
JAG1 | ENST00000617965.2 | n.3062C>T | non_coding_transcript_exon_variant | 15/17 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251368Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135864
GnomAD3 exomes
AF:
AC:
1
AN:
251368
Hom.:
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AC XY:
1
AN XY:
135864
Gnomad AFR exome
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GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Alagille syndrome due to a JAG1 point mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 04, 2017 | This variant has been reported in individuals affected with Alagille syndrome (PMID: 9585603, 26076142). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln825*) 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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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