rs147809756
Positions:
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP6_Very_StrongBS1BS2
The NM_000214.3(JAG1):c.2231G>A(p.Arg744Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,612,916 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00071 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0010 ( 3 hom. )
Consequence
JAG1
NM_000214.3 missense
NM_000214.3 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 4.76
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 -15 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, JAG1
BP6
?
Variant 20-10644976-C-T is Benign according to our data. Variant chr20-10644976-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 337752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10644976-C-T is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000706 (107/151572) while in subpopulation SAS AF= 0.00146 (7/4790). AF 95% confidence interval is 0.000904. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 107 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.2231G>A | p.Arg744Gln | missense_variant | 18/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.2231G>A | p.Arg744Gln | missense_variant | 18/26 | 1 | NM_000214.3 | P1 | |
JAG1 | ENST00000423891.6 | n.2097G>A | non_coding_transcript_exon_variant | 16/25 | 2 | ||||
JAG1 | ENST00000488480.2 | n.628G>A | non_coding_transcript_exon_variant | 4/4 | 4 | ||||
JAG1 | ENST00000617965.2 | n.2820G>A | non_coding_transcript_exon_variant | 12/17 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000706 AC: 107AN: 151454Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000946 AC: 238AN: 251478Hom.: 0 AF XY: 0.00116 AC XY: 157AN XY: 135912
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GnomAD4 exome AF: 0.00105 AC: 1529AN: 1461344Hom.: 3 Cov.: 31 AF XY: 0.00112 AC XY: 811AN XY: 727036
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GnomAD4 genome ? AF: 0.000706 AC: 107AN: 151572Hom.: 0 Cov.: 33 AF XY: 0.000567 AC XY: 42AN XY: 74072
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:2Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | JAG1: BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 17, 2018 | This variant is associated with the following publications: (PMID: 11139239, 10220506, 11157803, 11058898, 26760175) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 13, 2017 | - - |
Isolated Nonsyndromic Congenital Heart Disease Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Alagille syndrome due to a JAG1 point mutation Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Tetralogy of Fallot;C1866053:Deafness, congenital heart defects, and posterior embryotoxon;C1956125:Alagille syndrome due to a JAG1 point mutation;C5562003:Charcot-Marie-Tooth disease, axonal, Type 2HH Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
JAG1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 31, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
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
DS_AL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at