Variant rs2273060 details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000254958.10(JAG1):c.440-15T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,612,316 control chromosomes in the GnomAD database, including 138,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14149 hom., cov: 33)

Exomes 𝑓: 0.41 ( 124191 hom. )

Consequence

JAG1
ENST00000254958.10 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.853

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=-0.83).

BP6

Variant 20-10658737-A-G is Benign according to our data. Variant chr20-10658737-A-G is described in ClinVar as [Benign]. Clinvar id is 213524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10658737-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.488 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.440-15T>C		splice_polypyrimidine_tract_variant, intron_variant		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.440-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000214.3	ENSP00000254958	P1	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.306-15T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.432

AC:

65581

AN:

151978

Hom.:

14117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.473

Gnomad ASJ

AF:

0.444

Gnomad EAS

AF:

0.431

Gnomad SAS

AF:

0.505

Gnomad FIN

AF:

0.401

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.433

GnomAD3 exomes

AF:

0.439

AC:

109961

AN:

250398

Hom.:

24709

AF XY:

0.440

AC XY:

59613

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.460

Gnomad AMR exome

AF:

0.509

Gnomad ASJ exome

AF:

0.435

Gnomad EAS exome

AF:

0.433

Gnomad SAS exome

AF:

0.511

Gnomad FIN exome

AF:

0.401

Gnomad NFE exome

AF:

0.405

Gnomad OTH exome

AF:

0.424

GnomAD4 exome

AF:

0.410

AC:

598212

AN:

1460220

Hom.:

124191

Cov.:

AF XY:

0.412

AC XY:

299631

AN XY:

726526

show subpopulations

Gnomad4 AFR exome

AF:

0.467

Gnomad4 AMR exome

AF:

0.502

Gnomad4 ASJ exome

AF:

0.435

Gnomad4 EAS exome

AF:

0.433

Gnomad4 SAS exome

AF:

0.505

Gnomad4 FIN exome

AF:

0.402

Gnomad4 NFE exome

AF:

0.395

Gnomad4 OTH exome

AF:

0.422

GnomAD4 genome

AF:

0.432

AC:

65674

AN:

152096

Hom.:

14149

Cov.:

AF XY:

0.433

AC XY:

32201

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.461

Gnomad4 AMR

AF:

0.473

Gnomad4 ASJ

AF:

0.444

Gnomad4 EAS

AF:

0.430

Gnomad4 SAS

AF:

0.504

Gnomad4 FIN

AF:

0.401

Gnomad4 NFE

AF:

0.404

Gnomad4 OTH

AF:

0.435

Alfa

AF:

0.409

Hom.:

14241

Bravo

AF:

0.433

Asia WGS

AF:

0.512

AC:

1783

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

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

- -

Tetralogy of Fallot

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.4

DANN

Benign

0.36

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