NM_000214.3:c.744A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr20-10656409-T-C is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.0723

AC:

18171

AN:

251246

Hom.:

798

AF XY:

0.0694

AC XY:

9430

AN XY:

135806

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 SAS exome

AF:

0.0598

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

Gnomad4 AFR exome

AF:

0.0585

Gnomad4 AMR exome

AF:

0.121

Gnomad4 ASJ exome

AF:

0.0116

Gnomad4 EAS exome

AF:

0.0196

Gnomad4 SAS exome

AF:

0.0582

Gnomad4 FIN exome

AF:

0.0872

Gnomad4 NFE exome

AF:

0.0764

Gnomad4 OTH exome

AF:

0.0629

GnomAD4 genome

AF:

0.0683

AC:

10403

AN:

152336

Hom.:

393

Cov.:

AF XY:

0.0679

AC XY:

5059

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0565

Gnomad4 AMR

AF:

0.0932

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.0145

Gnomad4 SAS

AF:

0.0503

Gnomad4 FIN

AF:

0.0796

Gnomad4 NFE

AF:

0.0770

Gnomad4 OTH

AF:

0.0573

Alfa

AF:

0.0661

Hom.:

636

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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

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

- -

not provided

Benign:2

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

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

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

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over