rs1801138

Variant summary

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

The NM_000214.3(JAG1):c.588C>T(p.Cys196=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0705 in 1,614,084 control chromosomes in the GnomAD database, including 7,656 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. C196?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.11 ( 1516 hom., cov: 33)

Exomes 𝑓: 0.066 ( 6140 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.92

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=-0.53).

BP6

Variant 20-10658574-G-A is Benign according to our data. Variant chr20-10658574-G-A is described in ClinVar as [Benign]. Clinvar id is 42481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10658574-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 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.588C>T	p.Cys196=	synonymous_variant	4/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10 linkuse as main transcript	c.588C>T	p.Cys196=	synonymous_variant	4/26	1	NM_000214.3	P1	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.454C>T		non_coding_transcript_exon_variant	2/25	2

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16720

AN:

152106

Hom.:

1487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.0950

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.0423

Gnomad OTH

AF:

0.102

GnomAD3 exomes

AF:

0.106

AC:

26650

AN:

251446

Hom.:

2334

AF XY:

0.106

AC XY:

14462

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.227

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.0936

Gnomad EAS exome

AF:

0.236

Gnomad SAS exome

AF:

0.214

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0451

Gnomad OTH exome

AF:

0.0891

GnomAD4 exome

AF:

0.0664

AC:

97031

AN:

1461858

Hom.:

6140

Cov.:

AF XY:

0.0699

AC XY:

50834

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.233

Gnomad4 AMR exome

AF:

0.140

Gnomad4 ASJ exome

AF:

0.0936

Gnomad4 EAS exome

AF:

0.244

Gnomad4 SAS exome

AF:

0.209

Gnomad4 FIN exome

AF:

0.0224

Gnomad4 NFE exome

AF:

0.0409

Gnomad4 OTH exome

AF:

0.0892

GnomAD4 genome

AF:

0.110

AC:

16799

AN:

152226

Hom.:

1516

Cov.:

AF XY:

0.111

AC XY:

8281

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.223

Gnomad4 AMR

AF:

0.107

Gnomad4 ASJ

AF:

0.0950

Gnomad4 EAS

AF:

0.220

Gnomad4 SAS

AF:

0.214

Gnomad4 FIN

AF:

0.0190

Gnomad4 NFE

AF:

0.0423

Gnomad4 OTH

AF:

0.101

Alfa

AF:

0.0635

Hom.:

1025

Bravo

AF:

0.122

Asia WGS

AF:

0.213

AC:

740

AN:

3478

EpiCase

AF:

0.0537

EpiControl

AF:

0.0533

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 06, 2019	The p.Cys196Cys variant in JAG1 is classified as benign because it has been identified in 10.5% (29790/282820) of chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP4, BP7. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Isolated Nonsyndromic Congenital Heart Disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Alagille syndrome due to a JAG1 point mutation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

literature only

Department of Ophthalmology and Visual Sciences Kyoto University

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 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

-0.53

Cadd

Benign

Dann

Benign

0.91

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