rs1131695

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.765C>T(p.Tyr255Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,802 control chromosomes in the GnomAD database, including 168,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14538 hom., cov: 31)

Exomes 𝑓: 0.46 ( 153603 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.608

Publications

28 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=-0.72).

BP6

Variant 20-10652589-G-A is Benign according to our data. Variant chr20-10652589-G-A is described in ClinVar as Benign. ClinVar VariationId is 143063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.608 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.765C>T	p.Tyr255Tyr	synonymous_variant	Exon 6 of 26	ENST00000254958.10	NP_000205.1	P78504-1Q99740

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAG1	ENST00000254958.10 link	c.765C>T	p.Tyr255Tyr	synonymous_variant	Exon 6 of 26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 link	n.631C>T		non_coding_transcript_exon_variant	Exon 4 of 25	2
JAG1	ENST00000617965.2 link	n.134C>T		non_coding_transcript_exon_variant	Exon 1 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.433

AC:

65758

AN:

151850

Hom.:

14527

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.593

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.503

Gnomad EAS

AF:

0.344

Gnomad SAS

AF:

0.534

Gnomad FIN

AF:

0.451

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.465

Gnomad OTH

AF:

0.467

GnomAD2 exomes

AF:

0.456

AC:

114409

AN:

250970

AF XY:

0.465

show subpopulations

Gnomad AFR exome

AF:

0.349

Gnomad AMR exome

AF:

0.444

Gnomad ASJ exome

AF:

0.501

Gnomad EAS exome

AF:

0.343

Gnomad FIN exome

AF:

0.451

Gnomad NFE exome

AF:

0.467

Gnomad OTH exome

AF:

0.472

GnomAD4 exome

AF:

0.456

AC:

666247

AN:

1460834

Hom.:

153603

Cov.:

AF XY:

0.460

AC XY:

334168

AN XY:

726734

show subpopulations

African (AFR)

AF:

0.357

AC:

11941

AN:

33472

American (AMR)

AF:

0.444

AC:

19845

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.495

AC:

12934

AN:

26118

East Asian (EAS)

AF:

0.326

AC:

12936

AN:

39668

South Asian (SAS)

AF:

0.532

AC:

45855

AN:

86224

European-Finnish (FIN)

AF:

0.448

AC:

23895

AN:

53304

Middle Eastern (MID)

AF:

0.561

AC:

3230

AN:

5756

European-Non Finnish (NFE)

AF:

0.457

AC:

507854

AN:

1111256

Other (OTH)

AF:

0.460

AC:

27757

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

18648

37296

55945

74593

93241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15148

30296

45444

60592

75740

<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:

0.433

AC:

65799

AN:

151968

Hom.:

14538

Cov.:

AF XY:

0.435

AC XY:

32318

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.354

AC:

14674

AN:

41434

American (AMR)

AF:

0.458

AC:

7000

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

1747

AN:

3472

East Asian (EAS)

AF:

0.344

AC:

1768

AN:

5146

South Asian (SAS)

AF:

0.533

AC:

2574

AN:

4832

European-Finnish (FIN)

AF:

0.451

AC:

4749

AN:

10530

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.465

AC:

31597

AN:

67984

Other (OTH)

AF:

0.468

AC:

979

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1887

3774

5662

7549

9436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

620

1240

1860

2480

3100

<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:

0.454

Hom.:

20563

Bravo

AF:

0.428

Asia WGS

AF:

0.460

AC:

1603

AN:

3478

EpiCase

AF:

0.475

EpiControl

AF:

0.474

ClinVar

Significance: Benign

Submissions summary: Benign:14

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Alagille syndrome due to a JAG1 point mutation

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated Nonsyndromic Congenital Heart Disease

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

- -

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 23, 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

-0.72

CADD

Benign

0.42

(source)

DANN

Benign

0.90

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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