rs56225585

Positions:

Variant summary

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

The NM_000214.3(JAG1):c.2382C>T(p.Ser794=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,512 control chromosomes in the GnomAD database, including 3,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 1626 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 1498 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.337

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=-0.48).

BP6

Variant 20-10643854-G-A is Benign according to our data. Variant chr20-10643854-G-A is described in ClinVar as [Benign]. Clinvar id is 42474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10643854-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.337 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 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.2382C>T	p.Ser794=	synonymous_variant	20/26	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.2382C>T	p.Ser794=	synonymous_variant	20/26	1	NM_000214.3	ENSP00000254958	P1	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.2248C>T		non_coding_transcript_exon_variant	18/25	2
JAG1	ENST00000617965.2 linkuse as main transcript	n.2971C>T		non_coding_transcript_exon_variant	14/17	5

Frequencies

GnomAD3 genomes

AF:

0.0821

AC:

12479

AN:

151956

Hom.:

1622

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0391

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.0703

GnomAD3 exomes

AF:

0.0230

AC:

5763

AN:

251072

Hom.:

689

AF XY:

0.0169

AC XY:

2291

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.294

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000916

Gnomad FIN exome

AF:

0.00227

Gnomad NFE exome

AF:

0.00218

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.00949

AC:

13875

AN:

1461438

Hom.:

1498

Cov.:

AF XY:

0.00828

AC XY:

6022

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.287

Gnomad4 AMR exome

AF:

0.0183

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00121

Gnomad4 FIN exome

AF:

0.00165

Gnomad4 NFE exome

AF:

0.00166

Gnomad4 OTH exome

AF:

0.0213

GnomAD4 genome

AF:

0.0822

AC:

12504

AN:

152074

Hom.:

1626

Cov.:

AF XY:

0.0796

AC XY:

5922

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.280

Gnomad4 AMR

AF:

0.0390

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00188

Gnomad4 OTH

AF:

0.0695

Alfa

AF:

0.0324

Hom.:

354

Bravo

AF:

0.0937

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 09, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 10, 2023	- -

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. -

Alagille syndrome due to a JAG1 point mutation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 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

-0.48

CADD

Benign

8.6

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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