20-10656409-T-C

Variant names:

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.744A>G(p.Pro248Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0727 in 1,613,022 control chromosomes in the GnomAD database, including 4,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P248P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.068 ( 393 hom., cov: 32)

Exomes 𝑓: 0.073 ( 4320 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.927

Publications

20 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=-0.53).

BP6

Variant 20-10656409-T-C is Benign according to our data. Variant chr20-10656409-T-C is described in ClinVar as [Benign]. Clinvar id is 42482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.927 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.744A>G	p.Pro248Pro	synonymous_variant	Exon 5 of 26	ENST00000254958.10	NP_000205.1	P78504-1Q99740

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10 link	c.744A>G	p.Pro248Pro	synonymous_variant	Exon 5 of 26	1	NM_000214.3	ENSP00000254958.4		P78504-1
JAG1	ENST00000423891.6 link	n.610A>G		non_coding_transcript_exon_variant	Exon 3 of 25	2

Frequencies

GnomAD3 genomes

AF:

0.0683

AC:

10392

AN:

152218

Hom.:

393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0565

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0929

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.0142

Gnomad SAS

AF:

0.0503

Gnomad FIN

AF:

0.0796

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0770

Gnomad OTH

AF:

0.0579

GnomAD2 exomes

AF:

0.0723

AC:

18171

AN:

251246

AF XY:

0.0694

show subpopulations

Gnomad AFR exome

AF:

0.0577

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.0837

Gnomad NFE exome

AF:

0.0759

Gnomad OTH exome

AF:

0.0637

GnomAD4 exome

AF:

0.0732

AC:

106913

AN:

1460686

Hom.:

4320

Cov.:

AF XY:

0.0720

AC XY:

52343

AN XY:

726724

show subpopulations

African (AFR)

AF:

0.0585

AC:

1959

AN:

33466

American (AMR)

AF:

0.121

AC:

5424

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

304

AN:

26120

East Asian (EAS)

AF:

0.0196

AC:

779

AN:

39692

South Asian (SAS)

AF:

0.0582

AC:

5015

AN:

86234

European-Finnish (FIN)

AF:

0.0872

AC:

4651

AN:

53366

Middle Eastern (MID)

AF:

0.0196

AC:

113

AN:

5764

European-Non Finnish (NFE)

AF:

0.0764

AC:

84873

AN:

1110972

Other (OTH)

AF:

0.0629

AC:

3795

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4586

9172

13757

18343

22929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0683

AC:

10403

AN:

152336

Hom.:

393

Cov.:

AF XY:

0.0679

AC XY:

5059

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0565

AC:

2351

AN:

41578

American (AMR)

AF:

0.0932

AC:

1427

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3468

East Asian (EAS)

AF:

0.0145

AC:

AN:

5188

South Asian (SAS)

AF:

0.0503

AC:

243

AN:

4828

European-Finnish (FIN)

AF:

0.0796

AC:

845

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0770

AC:

5235

AN:

68028

Other (OTH)

AF:

0.0573

AC:

121

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

503

1006

1509

2012

2515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0665

Hom.:

747

Bravo

AF:

0.0681

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

EpiCase

AF:

0.0671

EpiControl

AF:

0.0648

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

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

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

-0.53

CADD

Benign

0.99

(source)

DANN

Benign

0.75

PhyloP100

-0.93

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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20-10656409-T-C

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