rs1051421

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000214.3(JAG1):c.3528C>T(p.Tyr1176=) variant causes a synonymous change. The variant allele was found at a frequency of 0.253 in 1,614,010 control chromosomes in the GnomAD database, including 53,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4229 hom., cov: 33)

Exomes 𝑓: 0.26 ( 49160 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 5.44

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 20-10639627-G-A is Benign according to our data. Variant chr20-10639627-G-A is described in ClinVar as [Benign]. Clinvar id is 42478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10639627-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3 linkuse as main transcript	c.3528C>T	p.Tyr1176=	synonymous_variant	26/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10 linkuse as main transcript	c.3528C>T	p.Tyr1176=	synonymous_variant	26/26	1	NM_000214.3	P1	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.3394C>T		non_coding_transcript_exon_variant	24/25	2

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33775

AN:

152058

Hom.:

4232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.466

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.155

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.256

GnomAD3 exomes

AF:

0.243

AC:

61006

AN:

251472

Hom.:

7968

AF XY:

0.244

AC XY:

33122

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.145

Gnomad SAS exome

AF:

0.192

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.256

AC:

373983

AN:

1461834

Hom.:

49160

Cov.:

AF XY:

0.256

AC XY:

185971

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.273

Gnomad4 ASJ exome

AF:

0.296

Gnomad4 EAS exome

AF:

0.173

Gnomad4 SAS exome

AF:

0.195

Gnomad4 FIN exome

AF:

0.221

Gnomad4 NFE exome

AF:

0.269

Gnomad4 OTH exome

AF:

0.245

GnomAD4 genome

AF:

0.222

AC:

33770

AN:

152176

Hom.:

4229

Cov.:

AF XY:

0.220

AC XY:

16333

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.284

Gnomad4 ASJ

AF:

0.287

Gnomad4 EAS

AF:

0.155

Gnomad4 SAS

AF:

0.191

Gnomad4 FIN

AF:

0.216

Gnomad4 NFE

AF:

0.278

Gnomad4 OTH

AF:

0.257

Alfa

AF:

0.269

Hom.:

9187

Bravo

AF:

0.221

Asia WGS

AF:

0.169

AC:

590

AN:

3478

EpiCase

AF:

0.284

EpiControl

AF:

0.282

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2016	p.Tyr1176Tyr in exon 26 of JAG1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 28% (18682/66732) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1051421). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Alagille syndrome due to a JAG1 point mutation

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Isolated Nonsyndromic Congenital Heart Disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Deafness, congenital heart defects, and posterior embryotoxon

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Tetralogy of Fallot

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2015

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

-0.58

Cadd

Benign

7.8

Dann

Benign

0.95

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