rs1051415

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Clinical Significance

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

Conservation

PhyloP100: 0.106

Publications

18 publications found

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]

JAG1 links:

LINC01752 (HGNC:52540): (long intergenic non-protein coding RNA 1752)

LINC01752 links:

ENSG00000270792 (HGNC:):

ENSG00000270792 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 42476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.267G>A	p.Gly89Gly	synonymous_variant	Exon 2 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
JAG1	ENST00000254958.10 link	c.267G>A	p.Gly89Gly	synonymous_variant	Exon 2 of 26	1	NM_000214.3	ENSP00000254958.4
LINC01752	ENST00000667822.1 link	n.127C>T		non_coding_transcript_exon_variant	Exon 1 of 2
LINC01752	ENST00000716704.1 link	n.109C>T		non_coding_transcript_exon_variant	Exon 1 of 3
ENSG00000270792	ENST00000605292.5 link	n.-107C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0822

AC:

12504

AN:

152158

Hom.:

671

Cov.:

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

GnomAD2 exomes

AF:

0.0960

AC:

24042

AN:

250386

AF XY:

0.0924

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 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.:

AF XY:

0.105

AC XY:

76068

AN XY:

726764

show subpopulations

African (AFR)

AF:

0.0163

AC:

546

AN:

33478

American (AMR)

AF:

0.119

AC:

5319

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0353

AC:

923

AN:

26134

East Asian (EAS)

AF:

0.0753

AC:

2989

AN:

39700

South Asian (SAS)

AF:

0.0420

AC:

3624

AN:

86258

European-Finnish (FIN)

AF:

0.121

AC:

6358

AN:

52446

Middle Eastern (MID)

AF:

0.0231

AC:

133

AN:

5768

European-Non Finnish (NFE)

AF:

0.119

AC:

131847

AN:

1111998

Other (OTH)

AF:

0.0940

AC:

5674

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

8934

17868

26801

35735

44669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4778

9556

14334

19112

23890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0822

AC:

12513

AN:

152276

Hom.:

672

Cov.:

AF XY:

0.0807

AC XY:

6010

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0213

AC:

886

AN:

41566

American (AMR)

AF:

0.0960

AC:

1469

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3472

East Asian (EAS)

AF:

0.111

AC:

574

AN:

5156

South Asian (SAS)

AF:

0.0364

AC:

176

AN:

4832

European-Finnish (FIN)

AF:

0.114

AC:

1204

AN:

10602

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7853

AN:

68020

Other (OTH)

AF:

0.0690

AC:

146

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

619

1237

1856

2474

3093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.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). -

not provided

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Isolated Nonsyndromic Congenital Heart Disease

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Sep 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 12, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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

(source)

DANN

Benign

0.94

PhyloP100

0.11

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over