rs45575136

Positions:

chr20-10652213-G-A

Variant summary

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

The NM_000214.3(JAG1):c.924C>T(p.Asn308=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,613,892 control chromosomes in the GnomAD database, including 933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 84 hom., cov: 32)

Exomes 𝑓: 0.029 ( 849 hom. )

Consequence

JAG1
NM_000214.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0580

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=-0.57).

BP6

Variant 20-10652213-G-A is Benign according to our data. Variant chr20-10652213-G-A is described in ClinVar as [Benign]. Clinvar id is 42483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10652213-G-A is described in Lovd as [Benign]. Variant chr20-10652213-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.058 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0658 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.924C>T	p.Asn308=	synonymous_variant	7/26	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.924C>T	p.Asn308=	synonymous_variant	7/26	1	NM_000214.3	ENSP00000254958	P1	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.790C>T		non_coding_transcript_exon_variant	5/25	2
JAG1	ENST00000617965.2 linkuse as main transcript	n.293C>T		non_coding_transcript_exon_variant	2/17	5

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3743

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00655

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0689

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0135

Gnomad SAS

AF:

0.0418

Gnomad FIN

AF:

0.0328

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0273

GnomAD3 exomes

AF:

0.0371

AC:

9328

AN:

251388

Hom.:

287

AF XY:

0.0348

AC XY:

4723

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.0113

Gnomad SAS exome

AF:

0.0435

Gnomad FIN exome

AF:

0.0349

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0298

GnomAD4 exome

AF:

0.0291

AC:

42533

AN:

1461668

Hom.:

849

Cov.:

AF XY:

0.0290

AC XY:

21072

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00505

Gnomad4 AMR exome

AF:

0.104

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.0169

Gnomad4 SAS exome

AF:

0.0422

Gnomad4 FIN exome

AF:

0.0333

Gnomad4 NFE exome

AF:

0.0270

Gnomad4 OTH exome

AF:

0.0250

GnomAD4 genome

AF:

0.0246

AC:

3747

AN:

152224

Hom.:

Cov.:

AF XY:

0.0259

AC XY:

1930

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00653

Gnomad4 AMR

AF:

0.0693

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.0137

Gnomad4 SAS

AF:

0.0412

Gnomad4 FIN

AF:

0.0328

Gnomad4 NFE

AF:

0.0254

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0229

Hom.:

Bravo

AF:

0.0265

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0243

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2016	p.Asn308Asn in exon 7 of JAG1:This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 11% (1274/11536) of Latino chromosomes, including 73 homozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45575136). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

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

-0.57

CADD

Benign

3.1

DANN

Benign

0.88

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