rs147809756

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000214.3(JAG1):c.2231G>A(p.Arg744Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,612,916 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

JAG1
NM_000214.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:9

Conservation

PhyloP100: 4.76

Publications

13 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 -16 ACMG points.

BP6

Variant 20-10644976-C-T is Benign according to our data. Variant chr20-10644976-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000706 (107/151572) while in subpopulation SAS AF = 0.00146 (7/4790). AF 95% confidence interval is 0.000904. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.2231G>A	p.Arg744Gln	missense_variant	Exon 18 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.2231G>A	p.Arg744Gln	missense_variant	Exon 18 of 26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 link	n.2097G>A		non_coding_transcript_exon_variant	Exon 16 of 25	2
JAG1	ENST00000488480.2 link	n.628G>A		non_coding_transcript_exon_variant	Exon 4 of 4	4
JAG1	ENST00000617965.2 link	n.2820G>A		non_coding_transcript_exon_variant	Exon 12 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.000706

AC:

107

AN:

151454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000919

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00327

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.000946

AC:

238

AN:

251478

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00105

AC:

1529

AN:

1461344

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

811

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33472

American (AMR)

AF:

0.00134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00146

AC:

126

AN:

86256

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00111

AC:

1238

AN:

1111492

Other (OTH)

AF:

0.00128

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000706

AC:

107

AN:

151572

Hom.:

Cov.:

AF XY:

0.000567

AC XY:

AN XY:

74072

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41336

American (AMR)

AF:

0.000918

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5028

South Asian (SAS)

AF:

0.00146

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00111

AC:

AN:

67836

Other (OTH)

AF:

0.00143

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00113

Hom.:

Bravo

AF:

0.000793

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Dec 17, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11139239, 10220506, 11157803, 11058898, 26760175) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

JAG1: BS1 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 13, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

JAG1-related disorder

Benign:1

Jan 31, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Apr 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 22, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

M_CAP

Benign

0.049

MetaRNN

Benign

0.041

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.7

PhyloP100

4.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.30

Sift

Uncertain

0.029

Sift4G

Benign

0.16

Polyphen

0.57

Vest4

0.48

MVP

0.76

MPC

0.59

ClinPred

0.027

GERP RS

6.1

Varity_R

0.17

gMVP

0.60

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: 3

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