rs143966918
Variant names:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_000214.3(JAG1):āc.3467T>Cā(p.Val1156Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00013 ( 0 hom., cov: 33)
Exomes š: 0.00014 ( 0 hom. )
Consequence
JAG1
NM_000214.3 missense
NM_000214.3 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 5.35
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 Benign. Variant got -10 ACMG points.
PP2
Missense variant in the JAG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 65 curated benign missense variants. Gene score misZ: 3.2459 (above the threshold of 3.09). Trascript score misZ: 5.2848 (above the threshold of 3.09). GenCC associations: The gene is linked to tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation, Charcot-Marie-Tooth disease, axonal, Type 2HH.
BP4
Computational evidence support a benign effect (MetaRNN=0.17765579).
BP6
Variant 20-10639688-A-G is Benign according to our data. Variant chr20-10639688-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424319.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr20-10639688-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000131 (20/152162) while in subpopulation NFE AF= 0.000265 (18/68028). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 20 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152162Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251478Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135916
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GnomAD4 exome AF: 0.000142 AC: 208AN: 1461894Hom.: 0 Cov.: 34 AF XY: 0.000140 AC XY: 102AN XY: 727248
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74346
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2017 | The V1156A variant in the JAG1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1156A variant is observed in 1/6614 (0.015%) alleles from individuals of Finnish background in the ExAC dataset (Lek et al., 2016). The V1156A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V1156A as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 12, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | JAG1: BS2 - |
Tetralogy of Fallot;C1866053:Deafness, congenital heart defects, and posterior embryotoxon;C1956125:Alagille syndrome due to a JAG1 point mutation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Alagille syndrome due to a JAG1 point mutation Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
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