rs1801140

Variant names:

• chr20-10645156-T-G
• rs1801140
• NM_000214.3:c.2214A>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000214.3(JAG1):​c.2214A>C​(p.Thr738Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,222 control chromosomes in the GnomAD database, including 9,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (698 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8696 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.89

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-10645156-T-G is Benign according to our data. Variant chr20-10645156-T-G is described in ClinVar as [Benign]. Clinvar id is 42473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10645156-T-G is described in Lovd as [Benign]. Variant chr20-10645156-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2214A>C	p.Thr738Thr	synonymous_variant	Exon 17 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2214A>C	p.Thr738Thr	synonymous_variant	Exon 17 of 26	1	NM_000214.3	ENSP00000254958.4

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13368 AN: 152126 Hom.: 698 Cov.: 33

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.0971

GnomAD3 exomes AF: 0.111 AC: 27930 AN: 251464 Hom.: 1866 AF XY: 0.115 AC XY: 15638 AN XY: 135900

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.0793

Gnomad EAS exome AF: 0.0456

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0985

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.103 AC: 150737 AN: 1460978 Hom.: 8696 Cov.: 31 AF XY: 0.106 AC XY: 76954 AN XY: 726836

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.0799

Gnomad4 EAS exome AF: 0.0427

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.0981

Gnomad4 OTH exome AF: 0.0988

GnomAD4 genome AF: 0.0880 AC: 13400 AN: 152244 Hom.: 698 Cov.: 33 AF XY: 0.0909 AC XY: 6768 AN XY: 74436

Gnomad4 AFR AF: 0.0355

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.0818

Gnomad4 EAS AF: 0.0451

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.0989

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0882 Hom.: 319

Bravo AF: 0.0833

Asia WGS AF: 0.153 AC: 533 AN: 3478

EpiCase AF: 0.0992

EpiControl AF: 0.0952

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Apr 10, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

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. -

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

Jun 29, 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	-0.86
CADD	Benign	0.20
DANN	Benign	0.44

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: rs1801140; hg19: chr20-10625804; COSMIC: COSV105039752; COSMIC: COSV105039752;