20-10641853-G-C

Position:

chr20-10641853-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000214.3(JAG1):c.2612C>G(p.Pro871Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0657 in 1,613,100 control chromosomes in the GnomAD database, including 4,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 252 hom., cov: 33)

Exomes 𝑓: 0.067 ( 3997 hom. )

Consequence

JAG1
NM_000214.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.05

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), JAG1. . Gene score misZ: 3.2459 (greater than the threshold 3.09). Trascript score misZ: 5.2848 (greater than threshold 3.09). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 65 curated benign missense variants. GenCC has associacion of the gene with tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation, Charcot-Marie-Tooth disease, axonal, Type 2HH.

BP4

Computational evidence support a benign effect (MetaRNN=0.001998365).

BP6

Variant 20-10641853-G-C is Benign according to our data. Variant chr20-10641853-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 42475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10641853-G-C is described in Lovd as [Likely_benign]. Variant chr20-10641853-G-C is described in Lovd as [Benign]. Variant chr20-10641853-G-C is described in Lovd as [Likely_pathogenic]. Variant chr20-10641853-G-C is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.2612C>G	p.Pro871Arg	missense_variant	22/26	ENST00000254958.10	NP_000205.1	P78504-1Q99740

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
JAG1	ENST00000254958.10 link	c.2612C>G	p.Pro871Arg	missense_variant	22/26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 link	n.2478C>G		non_coding_transcript_exon_variant	20/25	2
JAG1	ENST00000617965.2 link	n.3201C>G		non_coding_transcript_exon_variant	16/17	5

Frequencies

GnomAD3 genomes

AF:

0.0508

AC:

7726

AN:

152166

Hom.:

255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0335

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0294

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.0823

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0692

Gnomad OTH

AF:

0.0449

GnomAD3 exomes

AF:

0.0634

AC:

15942

AN:

251368

Hom.:

746

AF XY:

0.0693

AC XY:

9418

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0207

Gnomad EAS exome

AF:

0.0329

Gnomad SAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.0814

Gnomad NFE exome

AF:

0.0669

Gnomad OTH exome

AF:

0.0595

GnomAD4 exome

AF:

0.0673

AC:

98286

AN:

1460816

Hom.:

3997

Cov.:

AF XY:

0.0694

AC XY:

50428

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.0114

Gnomad4 AMR exome

AF:

0.0203

Gnomad4 ASJ exome

AF:

0.0203

Gnomad4 EAS exome

AF:

0.0280

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.0847

Gnomad4 NFE exome

AF:

0.0673

Gnomad4 OTH exome

AF:

0.0590

GnomAD4 genome

AF:

0.0508

AC:

7732

AN:

152284

Hom.:

252

Cov.:

AF XY:

0.0515

AC XY:

3832

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.0335

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.0289

Gnomad4 SAS

AF:

0.136

Gnomad4 FIN

AF:

0.0823

Gnomad4 NFE

AF:

0.0692

Gnomad4 OTH

AF:

0.0487

Alfa

AF:

0.0584

Hom.:

Bravo

AF:

0.0421

TwinsUK

AF:

0.0663

AC:

246

ALSPAC

AF:

0.0649

AC:

250

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.0653

AC:

562

ExAC

AF:

0.0662

AC:

8031

Asia WGS

AF:

0.100

AC:

348

AN:

3478

EpiCase

AF:

0.0646

EpiControl

AF:

0.0605

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Sep 03, 2010	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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

Mar 06, 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

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.56

Sift

Uncertain

0.011

Sift4G

Uncertain

0.024

Polyphen

0.99

Vest4

0.26

MPC

0.63

ClinPred

0.034

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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