rs1801138

Variant names:

• chr20-10658574-G-A
• rs1801138
• NM_000214.3:c.588C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-10658574-G-A
• chr20-10658574-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.588C>T​(p.Cys196Cys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0705 in 1,614,084 control chromosomes in the GnomAD database, including 7,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1516 hom., cov: 33)
  • Exomes 𝑓: 0.066 (6140 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.92

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-10658574-G-A is Benign according to our data. Variant chr20-10658574-G-A is described in ClinVar as [Benign]. Clinvar id is 42481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10658574-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.588C>T	p.Cys196Cys	synonymous_variant	Exon 4 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.588C>T	p.Cys196Cys	synonymous_variant	Exon 4 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.454C>T		non_coding_transcript_exon_variant	Exon 2 of 25	2

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16720 AN: 152106 Hom.: 1487 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.106 AC: 26650 AN: 251446 Hom.: 2334 AF XY: 0.106 AC XY: 14462 AN XY: 135896

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.0936

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0451

Gnomad OTH exome AF: 0.0891

GnomAD4 exome AF: 0.0664 AC: 97031 AN: 1461858 Hom.: 6140 Cov.: 34 AF XY: 0.0699 AC XY: 50834 AN XY: 727230

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.0936

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.0224

Gnomad4 NFE exome AF: 0.0409

Gnomad4 OTH exome AF: 0.0892

GnomAD4 genome AF: 0.110 AC: 16799 AN: 152226 Hom.: 1516 Cov.: 33 AF XY: 0.111 AC XY: 8281 AN XY: 74426

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.0950

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.0423

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0635 Hom.: 1025

Bravo AF: 0.122

Asia WGS AF: 0.213 AC: 740 AN: 3478

EpiCase AF: 0.0537

EpiControl AF: 0.0533

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

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

- -

May 06, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys196Cys variant in JAG1 is classified as benign because it has been identified in 10.5% (29790/282820) of chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP4, BP7. -

May 28, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Alagille syndrome due to a JAG1 point mutation Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 15, 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	-0.53
CADD	Benign	10
DANN	Benign	0.91
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

Other links and lift over

dbSNP: rs1801138; hg19: chr20-10639222; COSMIC: COSV54757520;