20-10639738-A-G

Variant names:

• chr20-10639738-A-G
• rs1051419
• NM_000214.3:c.3417T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000214.3(JAG1):​c.3417T>C​(p.Tyr1139Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,856 control chromosomes in the GnomAD database, including 342,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39477 hom., cov: 32)
  • Exomes 𝑓: 0.64 (302723 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.470
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• Alagille syndrome due to a JAG1 point mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 20-10639738-A-G is Benign according to our data. Variant chr20-10639738-A-G is described in ClinVar as Benign. ClinVar VariationId is 137595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.3417T>C	p.Tyr1139Tyr	synonymous_variant	Exon 26 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.3417T>C	p.Tyr1139Tyr	synonymous_variant	Exon 26 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.3283T>C		non_coding_transcript_exon_variant	Exon 24 of 25	2
JAG1	ENST00000617357.1	n.*132T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107636 AN: 152002 Hom.: 39419 Cov.: 32

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.707

GnomAD2 exomes AF: 0.651 AC: 163796 AN: 251484 AF XY: 0.653

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.639

GnomAD4 exome AF: 0.640 AC: 935653 AN: 1461736 Hom.: 302723 Cov.: 48 AF XY: 0.643 AC XY: 467708 AN XY: 727188

African (AFR) AF: 0.909 AC: 30427 AN: 33480

American (AMR) AF: 0.639 AC: 28595 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 15828 AN: 26136

East Asian (EAS) AF: 0.428 AC: 17011 AN: 39700

South Asian (SAS) AF: 0.765 AC: 65951 AN: 86258

European-Finnish (FIN) AF: 0.577 AC: 30842 AN: 53416

Middle Eastern (MID) AF: 0.646 AC: 3728 AN: 5768

European-Non Finnish (NFE) AF: 0.634 AC: 704511 AN: 1111868

Other (OTH) AF: 0.642 AC: 38760 AN: 60386

GnomAD4 genome AF: 0.708 AC: 107755 AN: 152120 Hom.: 39477 Cov.: 32 AF XY: 0.705 AC XY: 52450 AN XY: 74354

African (AFR) AF: 0.901 AC: 37405 AN: 41524

American (AMR) AF: 0.684 AC: 10458 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2067 AN: 3468

East Asian (EAS) AF: 0.444 AC: 2288 AN: 5154

South Asian (SAS) AF: 0.765 AC: 3686 AN: 4816

European-Finnish (FIN) AF: 0.569 AC: 6021 AN: 10578

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43440 AN: 67984

Other (OTH) AF: 0.706 AC: 1492 AN: 2112

Alfa AF: 0.663 Hom.: 32042

Bravo AF: 0.716

Asia WGS AF: 0.629 AC: 2189 AN: 3478

EpiCase AF: 0.641

EpiControl AF: 0.643

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 30, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Alagille syndrome due to a JAG1 point mutation Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

JAG1-related disorder Benign:1

Feb 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Tetralogy of Fallot Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jun 12, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.73
CADD	Benign	0.49
DANN	Benign	0.59
PhyloP100		-0.47
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1051419; hg19: chr20-10620386; COSMIC: COSV54753151; COSMIC: COSV54753151;