20-10641566-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000214.3(JAG1):c.2810G>A(p.Arg937Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,614,150 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R937W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 7 hom. )

Consequence

JAG1
NM_000214.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.49

Publications

22 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 (MetaRNN=0.01222077).

BP6

Variant 20-10641566-C-T is Benign according to our data. Variant chr20-10641566-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00186 (284/152292) while in subpopulation AMR AF = 0.00425 (65/15304). AF 95% confidence interval is 0.00342. There are 0 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 284 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.2810G>A	p.Arg937Gln	missense_variant	Exon 23 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.2810G>A	p.Arg937Gln	missense_variant	Exon 23 of 26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 link	n.2676G>A		non_coding_transcript_exon_variant	Exon 21 of 25	2
JAG1	ENST00000617965.2 link	n.*14G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00237

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00192

AC:

483

AN:

251308

AF XY:

0.00221

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00507

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00239

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00221

AC:

3229

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

1638

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.00134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00517

AC:

135

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00341

AC:

294

AN:

86256

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00230

AC:

2555

AN:

1112004

Other (OTH)

AF:

0.00245

AC:

148

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00186

AC:

284

AN:

152292

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41558

American (AMR)

AF:

0.00425

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00291

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00237

AC:

161

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00167

Hom.:

Bravo

AF:

0.00218

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00217

AC:

263

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

JAG1: PP2, BP4, BS1 -

Feb 13, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12497640, 20437614, 26760175, 25260786, 22040217, 19948535, 23956173, 28444304) -

not specified

Benign:3

Nov 23, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2019

Genetic Services Laboratory, University of Chicago

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

- -

Alagille syndrome due to a JAG1 point mutation

Benign:3

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Benign, for Alagille syndrome 1, autosomal dominant. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/20437614). -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 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

Mar 06, 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. -

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 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 20, 2017

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

0.081

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.023

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.13

PhyloP100

3.5

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.74

REVEL

Uncertain

0.44

Sift

Benign

0.31

Sift4G

Benign

0.54

Polyphen

0.093

Vest4

0.71

MVP

0.97

MPC

0.53

ClinPred

0.0087

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.068

gMVP

0.44

Mutation Taster

=79/21

polymorphism

(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