Variant chr20-10639738-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000254958.10(JAG1):c.3417T>C(p.Tyr1139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,856 control chromosomes in the GnomAD database, including 342,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 39477 hom., cov: 32)

Exomes 𝑓: 0.64 ( 302723 hom. )

Consequence

JAG1
ENST00000254958.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.470

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=-0.73).

BP6

Variant 20-10639738-A-G is Benign according to our data. Variant chr20-10639738-A-G is described in ClinVar as [Benign]. Clinvar id is 137595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10639738-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.47 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3 linkuse as main transcript	c.3417T>C	p.Tyr1139=	synonymous_variant	26/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10 linkuse as main transcript	c.3417T>C	p.Tyr1139=	synonymous_variant	26/26	1	NM_000214.3	ENSP00000254958	P1	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.3283T>C		non_coding_transcript_exon_variant	24/25	2

Frequencies

GnomAD3 genomes

AF:

0.708

AC:

107636

AN:

152002

Hom.:

39419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.901

Gnomad AMI

AF:

0.771

Gnomad AMR

AF:

0.684

Gnomad ASJ

AF:

0.596

Gnomad EAS

AF:

0.444

Gnomad SAS

AF:

0.766

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.655

Gnomad NFE

AF:

0.639

Gnomad OTH

AF:

0.707

GnomAD3 exomes

AF:

0.651

AC:

163796

AN:

251484

Hom.:

54765

AF XY:

0.653

AC XY:

88727

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.905

Gnomad AMR exome

AF:

0.641

Gnomad ASJ exome

AF:

0.609

Gnomad EAS exome

AF:

0.432

Gnomad SAS exome

AF:

0.771

Gnomad FIN exome

AF:

0.575

Gnomad NFE exome

AF:

0.641

Gnomad OTH exome

AF:

0.639

GnomAD4 exome

AF:

0.640

AC:

935653

AN:

1461736

Hom.:

302723

Cov.:

AF XY:

0.643

AC XY:

467708

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.909

Gnomad4 AMR exome

AF:

0.639

Gnomad4 ASJ exome

AF:

0.606

Gnomad4 EAS exome

AF:

0.428

Gnomad4 SAS exome

AF:

0.765

Gnomad4 FIN exome

AF:

0.577

Gnomad4 NFE exome

AF:

0.634

Gnomad4 OTH exome

AF:

0.642

GnomAD4 genome

AF:

0.708

AC:

107755

AN:

152120

Hom.:

39477

Cov.:

AF XY:

0.705

AC XY:

52450

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.901

Gnomad4 AMR

AF:

0.684

Gnomad4 ASJ

AF:

0.596

Gnomad4 EAS

AF:

0.444

Gnomad4 SAS

AF:

0.765

Gnomad4 FIN

AF:

0.569

Gnomad4 NFE

AF:

0.639

Gnomad4 OTH

AF:

0.706

Alfa

AF:

0.661

Hom.:

23751

Bravo

AF:

0.716

Asia WGS

AF:

0.629

AC:

2189

AN:

3478

EpiCase

AF:

0.641

EpiControl

AF:

0.643

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2018	- -

Alagille syndrome due to a JAG1 point mutation

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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 13, 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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

JAG1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 12, 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

-0.73

CADD

Benign

0.49

DANN

Benign

0.59

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