rs1051415

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000214.3(JAG1):​c.267G>A​(p.Gly89Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,164 control chromosomes in the GnomAD database, including 10,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 672 hom., cov: 33)
Exomes 𝑓: 0.11 ( 9476 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.106
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 20-10672821-C-T is Benign according to our data. Variant chr20-10672821-C-T is described in ClinVar as [Benign]. Clinvar id is 42476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10672821-C-T is described in Lovd as [Benign]. Variant chr20-10672821-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.106 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JAG1NM_000214.3 linkuse as main transcriptc.267G>A p.Gly89Gly synonymous_variant 2/26 ENST00000254958.10 NP_000205.1 P78504-1Q99740

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JAG1ENST00000254958.10 linkuse as main transcriptc.267G>A p.Gly89Gly synonymous_variant 2/261 NM_000214.3 ENSP00000254958.4 P78504-1
ENSG00000270792ENST00000667822.1 linkuse as main transcriptn.127C>T non_coding_transcript_exon_variant 1/2

Frequencies

GnomAD3 genomes
AF:
0.0822
AC:
12504
AN:
152158
Hom.:
671
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0214
Gnomad AMI
AF:
0.0768
Gnomad AMR
AF:
0.0956
Gnomad ASJ
AF:
0.0369
Gnomad EAS
AF:
0.110
Gnomad SAS
AF:
0.0358
Gnomad FIN
AF:
0.114
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.115
Gnomad OTH
AF:
0.0702
GnomAD3 exomes
AF:
0.0960
AC:
24042
AN:
250386
Hom.:
1406
AF XY:
0.0924
AC XY:
12550
AN XY:
135758
show subpopulations
Gnomad AFR exome
AF:
0.0198
Gnomad AMR exome
AF:
0.120
Gnomad ASJ exome
AF:
0.0346
Gnomad EAS exome
AF:
0.113
Gnomad SAS exome
AF:
0.0415
Gnomad FIN exome
AF:
0.119
Gnomad NFE exome
AF:
0.113
Gnomad OTH exome
AF:
0.0899
GnomAD4 exome
AF:
0.108
AC:
157413
AN:
1460888
Hom.:
9476
Cov.:
35
AF XY:
0.105
AC XY:
76068
AN XY:
726764
show subpopulations
Gnomad4 AFR exome
AF:
0.0163
Gnomad4 AMR exome
AF:
0.119
Gnomad4 ASJ exome
AF:
0.0353
Gnomad4 EAS exome
AF:
0.0753
Gnomad4 SAS exome
AF:
0.0420
Gnomad4 FIN exome
AF:
0.121
Gnomad4 NFE exome
AF:
0.119
Gnomad4 OTH exome
AF:
0.0940
GnomAD4 genome
AF:
0.0822
AC:
12513
AN:
152276
Hom.:
672
Cov.:
33
AF XY:
0.0807
AC XY:
6010
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.0213
Gnomad4 AMR
AF:
0.0960
Gnomad4 ASJ
AF:
0.0369
Gnomad4 EAS
AF:
0.111
Gnomad4 SAS
AF:
0.0364
Gnomad4 FIN
AF:
0.114
Gnomad4 NFE
AF:
0.115
Gnomad4 OTH
AF:
0.0690
Alfa
AF:
0.0964
Hom.:
416
Bravo
AF:
0.0794
Asia WGS
AF:
0.0660
AC:
228
AN:
3478
EpiCase
AF:
0.102
EpiControl
AF:
0.0995

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 13, 2016p.Gly89Gly in exon 2 of JAG1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 12% (1394/11536) of Latino chromosomes, including 83 homozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1051415). -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 15, 2023Variant summary: JAG1 c.267G>A alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.095 in 281760 control chromosomes in the gnomAD database, including 1553 homozygotes. The observed variant frequency is approximately 4600 fold of the estimated maximal expected allele frequency for a pathogenic variant in JAG1 causing Alagille Syndrome 1 (2.1e-05), strongly suggesting that the variant is benign. Five ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:2
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Isolated Nonsyndromic Congenital Heart Disease Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 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
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 28, 2021- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 12, 2015This alteration is classified as 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Benign
12
DANN
Benign
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1051415; hg19: chr20-10653469; COSMIC: COSV54757776; COSMIC: COSV54757776; API