rs1131695

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.765C>T(p.Tyr255Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,802 control chromosomes in the GnomAD database, including 168,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14538 hom., cov: 31)

Exomes 𝑓: 0.46 ( 153603 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.608

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:

JAG1 (HGNC:):

JAG1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 20-10652589-G-A is Benign according to our data. Variant chr20-10652589-G-A is described in ClinVar as [Benign]. Clinvar id is 143063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10652589-G-A is described in Lovd as [Benign]. Variant chr20-10652589-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.608 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.516 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.765C>T	p.Tyr255Tyr	synonymous_variant	6/26	ENST00000254958.10	NP_000205.1	P78504-1Q99740

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
JAG1	ENST00000254958.10 linkuse as main transcript	c.765C>T	p.Tyr255Tyr	synonymous_variant	6/26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.631C>T		non_coding_transcript_exon_variant	4/25	2
JAG1	ENST00000617965.2 linkuse as main transcript	n.134C>T		non_coding_transcript_exon_variant	1/17	5

Frequencies

GnomAD3 genomes

AF:

0.433

AC:

65758

AN:

151850

Hom.:

14527

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.593

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.503

Gnomad EAS

AF:

0.344

Gnomad SAS

AF:

0.534

Gnomad FIN

AF:

0.451

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.465

Gnomad OTH

AF:

0.467

GnomAD3 exomes

AF:

0.456

AC:

114409

AN:

250970

Hom.:

26646

AF XY:

0.465

AC XY:

63116

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.349

Gnomad AMR exome

AF:

0.444

Gnomad ASJ exome

AF:

0.501

Gnomad EAS exome

AF:

0.343

Gnomad SAS exome

AF:

0.536

Gnomad FIN exome

AF:

0.451

Gnomad NFE exome

AF:

0.467

Gnomad OTH exome

AF:

0.472

GnomAD4 exome

AF:

0.456

AC:

666247

AN:

1460834

Hom.:

153603

Cov.:

AF XY:

0.460

AC XY:

334168

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.357

Gnomad4 AMR exome

AF:

0.444

Gnomad4 ASJ exome

AF:

0.495

Gnomad4 EAS exome

AF:

0.326

Gnomad4 SAS exome

AF:

0.532

Gnomad4 FIN exome

AF:

0.448

Gnomad4 NFE exome

AF:

0.457

Gnomad4 OTH exome

AF:

0.460

GnomAD4 genome

AF:

0.433

AC:

65799

AN:

151968

Hom.:

14538

Cov.:

AF XY:

0.435

AC XY:

32318

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.354

Gnomad4 AMR

AF:

0.458

Gnomad4 ASJ

AF:

0.503

Gnomad4 EAS

AF:

0.344

Gnomad4 SAS

AF:

0.533

Gnomad4 FIN

AF:

0.451

Gnomad4 NFE

AF:

0.465

Gnomad4 OTH

AF:

0.468

Alfa

AF:

0.458

Hom.:

13551

Bravo

AF:

0.428

Asia WGS

AF:

0.460

AC:

1603

AN:

3478

EpiCase

AF:

0.475

EpiControl

AF:

0.474

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

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. -

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 23, 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

-0.72

CADD

Benign

0.42

DANN

Benign

0.90

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