20-10641853-G-C

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.2612C>G(p.Pro871Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0657 in 1,613,100 control chromosomes in the GnomAD database, including 4,249 homozygotes. In-silico tool predicts 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. P871T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.051 ( 252 hom., cov: 33)

Exomes 𝑓: 0.067 ( 3997 hom. )

Consequence

JAG1
NM_000214.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.05

Publications

31 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=0.001998365).

BP6

Variant 20-10641853-G-C is Benign according to our data. Variant chr20-10641853-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.2612C>G	p.Pro871Arg	missense_variant	Exon 22 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.2612C>G	p.Pro871Arg	missense_variant	Exon 22 of 26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 link	n.2478C>G		non_coding_transcript_exon_variant	Exon 20 of 25	2
JAG1	ENST00000617965.2 link	n.3201C>G		non_coding_transcript_exon_variant	Exon 16 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.0508

AC:

7726

AN:

152166

Hom.:

255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0335

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0294

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.0823

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0692

Gnomad OTH

AF:

0.0449

GnomAD2 exomes

AF:

0.0634

AC:

15942

AN:

251368

AF XY:

0.0693

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0207

Gnomad EAS exome

AF:

0.0329

Gnomad FIN exome

AF:

0.0814

Gnomad NFE exome

AF:

0.0669

Gnomad OTH exome

AF:

0.0595

GnomAD4 exome

AF:

0.0673

AC:

98286

AN:

1460816

Hom.:

3997

Cov.:

AF XY:

0.0694

AC XY:

50428

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.0114

AC:

380

AN:

33468

American (AMR)

AF:

0.0203

AC:

908

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0203

AC:

531

AN:

26134

East Asian (EAS)

AF:

0.0280

AC:

1110

AN:

39698

South Asian (SAS)

AF:

0.143

AC:

12292

AN:

86226

European-Finnish (FIN)

AF:

0.0847

AC:

4523

AN:

53420

Middle Eastern (MID)

AF:

0.0394

AC:

227

AN:

5768

European-Non Finnish (NFE)

AF:

0.0673

AC:

74755

AN:

1111020

Other (OTH)

AF:

0.0590

AC:

3560

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

5081

10162

15242

20323

25404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2782

5564

8346

11128

13910

<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:

0.0508

AC:

7732

AN:

152284

Hom.:

252

Cov.:

AF XY:

0.0515

AC XY:

3832

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0140

AC:

584

AN:

41570

American (AMR)

AF:

0.0335

AC:

512

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.0289

AC:

150

AN:

5188

South Asian (SAS)

AF:

0.136

AC:

654

AN:

4822

European-Finnish (FIN)

AF:

0.0823

AC:

873

AN:

10608

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0692

AC:

4705

AN:

68006

Other (OTH)

AF:

0.0487

AC:

103

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

360

720

1079

1439

1799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0584

Hom.:

Bravo

AF:

0.0421

TwinsUK

AF:

0.0663

AC:

246

ALSPAC

AF:

0.0649

AC:

250

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.0653

AC:

562

ExAC

AF:

0.0662

AC:

8031

Asia WGS

AF:

0.100

AC:

348

AN:

3478

EpiCase

AF:

0.0646

EpiControl

AF:

0.0605

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 03, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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

- -

Feb 05, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

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. -

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 29, 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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.7

PhyloP100

5.0

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.56

Sift

Uncertain

0.011

Sift4G

Uncertain

0.024

Polyphen

0.99

Vest4

0.26

MPC

0.63

ClinPred

0.034

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.45

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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