rs397515876
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_000214.3(JAG1):c.3583A>G(p.Asn1195Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
JAG1
NM_000214.3 missense
NM_000214.3 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 4.99
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 Likely_benign. Variant got -6 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, JAG1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.25765678).
BP6
?
Variant 20-10639572-T-C is Benign according to our data. Variant chr20-10639572-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42479.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS2
?
High AC in GnomAd at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.3583A>G | p.Asn1195Asp | missense_variant | 26/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.3583A>G | p.Asn1195Asp | missense_variant | 26/26 | 1 | NM_000214.3 | P1 | |
JAG1 | ENST00000423891.6 | n.3449A>G | non_coding_transcript_exon_variant | 24/25 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152152Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251448Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727234
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74326
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 10, 2011 | The Asn1195Asp variant in JAG1 has not been reported in the literature. It has been detected by our laboratory in one individual of Black ancestry with suspect ed Alagille syndrome. This individual carried another, pathogenic varant in the JAG1 gene, making it difficult to predict the effect of the Asn1195Asp variant in isolation. Asparagine (Asn) at position 1195 is conserved evolutionarily dis tant species, indicating that a change may not be tolerated. However, it should be noted that this lab has sequenced the JAG1 gene in only a small number of Bla ck individuals and no Black healthy controls. In addition, healthy control infor mation is unavailable from either public databases or scientific literature, suc h that the full spectrum of benign variation has not yet been defined for this p opulation. Future analysis could therefore reveal that the Asn1195Asp variant is common unlikely to be pathogenic. In summary, the clinical significance of this variant cannot be determined at this time due to occurrence with another, patho genic variant as well as lack of control data. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2021 | The c.3583A>G (p.N1195D) alteration is located in exon 26 (coding exon 26) of the JAG1 gene. This alteration results from a A to G substitution at nucleotide position 3583, causing the asparagine (N) at amino acid position 1195 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Alagille syndrome due to a JAG1 point mutation Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Apr 01, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of phosphorylation at T1197 (P = 0.1003);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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