rs1051421

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000214.3(JAG1):c.3528C>T(p.Tyr1176Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.253 in 1,614,010 control chromosomes in the GnomAD database, including 53,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4229 hom., cov: 33)

Exomes 𝑓: 0.26 ( 49160 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.44

Publications

24 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 Gene-Disease associations (from GenCC):

Alagille syndrome due to a JAG1 point mutation
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
Charcot-Marie-Tooth disease, axonal, Type 2HH
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
tetralogy of fallot
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

JAG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 20-10639627-G-A is Benign according to our data. Variant chr20-10639627-G-A is described in ClinVar as Benign. ClinVar VariationId is 42478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.3528C>T	p.Tyr1176Tyr	synonymous_variant	Exon 26 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
JAG1	ENST00000254958.10 link	c.3528C>T	p.Tyr1176Tyr	synonymous_variant	Exon 26 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6 link	n.3394C>T		non_coding_transcript_exon_variant	Exon 24 of 25	2
JAG1	ENST00000617357.1 link	n.*243C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33775

AN:

152058

Hom.:

4232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.466

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.155

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.256

GnomAD2 exomes

AF:

0.243

AC:

61006

AN:

251472

AF XY:

0.244

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.256

AC:

373983

AN:

1461834

Hom.:

49160

Cov.:

AF XY:

0.256

AC XY:

185971

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.102

AC:

3401

AN:

33480

American (AMR)

AF:

0.273

AC:

12204

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

7732

AN:

26134

East Asian (EAS)

AF:

0.173

AC:

6862

AN:

39700

South Asian (SAS)

AF:

0.195

AC:

16853

AN:

86256

European-Finnish (FIN)

AF:

0.221

AC:

11785

AN:

53414

Middle Eastern (MID)

AF:

0.258

AC:

1490

AN:

5766

European-Non Finnish (NFE)

AF:

0.269

AC:

298889

AN:

1111966

Other (OTH)

AF:

0.245

AC:

14767

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

17455

34911

52366

69822

87277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9798

19596

29394

39192

48990

<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:

0.222

AC:

33770

AN:

152176

Hom.:

4229

Cov.:

AF XY:

0.220

AC XY:

16333

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.108

AC:

4495

AN:

41540

American (AMR)

AF:

0.284

AC:

4339

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

995

AN:

3470

East Asian (EAS)

AF:

0.155

AC:

801

AN:

5184

South Asian (SAS)

AF:

0.191

AC:

920

AN:

4824

European-Finnish (FIN)

AF:

0.216

AC:

2284

AN:

10592

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18890

AN:

67986

Other (OTH)

AF:

0.257

AC:

541

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1332

2665

3997

5330

6662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.265

Hom.:

10902

Bravo

AF:

0.221

Asia WGS

AF:

0.169

AC:

590

AN:

3478

EpiCase

AF:

0.284

EpiControl

AF:

0.282

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 04, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 30, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Tyr1176Tyr in exon 26 of JAG1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 28% (18682/66732) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1051421). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Alagille syndrome due to a JAG1 point mutation

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Deafness, congenital heart defects, and posterior embryotoxon

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Tetralogy of Fallot

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 24, 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

-0.58

CADD

Benign

7.8

(source)

DANN

Benign

0.95

PhyloP100

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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