rs876660980
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000214.3(JAG1):c.703C>T(p.Arg235Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,504 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
JAG1
NM_000214.3 stop_gained
NM_000214.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.61
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 20-10656450-G-A is Pathogenic according to our data. Variant chr20-10656450-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 234320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10656450-G-A is described in Lovd as [Pathogenic]. Variant chr20-10656450-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.703C>T | p.Arg235Ter | stop_gained | 5/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.703C>T | p.Arg235Ter | stop_gained | 5/26 | 1 | NM_000214.3 | P1 | |
JAG1 | ENST00000423891.6 | n.569C>T | non_coding_transcript_exon_variant | 3/25 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461504Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727064
GnomAD4 exome
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1
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1461504
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30
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1
AN XY:
727064
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | Nonsense variant predicted to result in 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: 25525159, 24748328, 27256232, 11139247, 26076142, 9585603, 29707407, 11180599, 31343788) - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 15, 2018 | - - |
Alagille syndrome due to a JAG1 point mutation Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 05, 2021 | PVS1, PM2, PP3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234320). This premature translational stop signal has been observed in individual(s) with Alagille syndrome (PMID: 9585603, 23891399, 24748328, 26076142). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg235*) 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). - |
JAG1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2023 | The JAG1 c.703C>T variant is predicted to result in premature protein termination (p.Arg235*). This variant has been previously reported in individuals with Alagille syndrome, in some cases occurring de novo (see for example Krantz et al. 1998. PubMed ID: 9585603; Colliton et al. 2001. PubMed ID: 11180599; Jurkiewicz et al 2014. PubMed ID: 24748328). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in JAG1 are expected to be pathogenic. This variant is interpreted 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