rs45575136

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000214.3(JAG1):c.924C>T(p.Asn308Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,613,892 control chromosomes in the GnomAD database, including 933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 84 hom., cov: 32)

Exomes 𝑓: 0.029 ( 849 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0580

Publications

11 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 20-10652213-G-A is Benign according to our data. Variant chr20-10652213-G-A is described in ClinVar as Benign. ClinVar VariationId is 42483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.058 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.924C>T	p.Asn308Asn	synonymous_variant	Exon 7 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
JAG1	ENST00000254958.10 link	c.924C>T	p.Asn308Asn	synonymous_variant	Exon 7 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6 link	n.790C>T		non_coding_transcript_exon_variant	Exon 5 of 25	2
JAG1	ENST00000617965.2 link	n.293C>T		non_coding_transcript_exon_variant	Exon 2 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3743

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00655

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0689

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0135

Gnomad SAS

AF:

0.0418

Gnomad FIN

AF:

0.0328

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0273

GnomAD2 exomes

AF:

0.0371

AC:

9328

AN:

251388

AF XY:

0.0348

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.0113

Gnomad FIN exome

AF:

0.0349

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0298

GnomAD4 exome

AF:

0.0291

AC:

42533

AN:

1461668

Hom.:

849

Cov.:

AF XY:

0.0290

AC XY:

21072

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00505

AC:

169

AN:

33476

American (AMR)

AF:

0.104

AC:

4652

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

26134

East Asian (EAS)

AF:

0.0169

AC:

671

AN:

39700

South Asian (SAS)

AF:

0.0422

AC:

3636

AN:

86256

European-Finnish (FIN)

AF:

0.0333

AC:

1780

AN:

53408

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0270

AC:

30014

AN:

1111822

Other (OTH)

AF:

0.0250

AC:

1507

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2404

4809

7213

9618

12022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1202

2404

3606

4808

6010

<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:

0.0246

AC:

3747

AN:

152224

Hom.:

Cov.:

AF XY:

0.0259

AC XY:

1930

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00653

AC:

271

AN:

41524

American (AMR)

AF:

0.0693

AC:

1059

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0137

AC:

AN:

5180

South Asian (SAS)

AF:

0.0412

AC:

199

AN:

4828

European-Finnish (FIN)

AF:

0.0328

AC:

348

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0254

AC:

1731

AN:

68022

Other (OTH)

AF:

0.0270

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

182

364

545

727

909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0229

Hom.:

Bravo

AF:

0.0265

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0243

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 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

- -

Feb 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn308Asn in exon 7 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 11% (1274/11536) of Latino chromosomes, including 73 homozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45575136). -

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 13, 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

- -

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

-0.57

CADD

Benign

3.1

(source)

DANN

Benign

0.88

PhyloP100

0.058

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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