rs45575136

Variant names:

• chr20-10652213-G-A
• rs45575136
• NM_000214.3:c.924C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-10652213-G-A
• chr20-10652213-G-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.924C>T​(p.Asn308Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,613,892 control chromosomes in the GnomAD database, including 933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (84 hom., cov: 32)
  • Exomes 𝑓: 0.029 (849 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0580

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=-0.57).
• BP6: Variant 20-10652213-G-A is Benign according to our data. Variant chr20-10652213-G-A is described in ClinVar as [Benign]. Clinvar id is 42483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10652213-G-A is described in Lovd as [Benign]. Variant chr20-10652213-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.058 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.924C>T	p.Asn308Asn	synonymous_variant	Exon 7 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.924C>T	p.Asn308Asn	synonymous_variant	Exon 7 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.790C>T		non_coding_transcript_exon_variant	Exon 5 of 25	2
JAG1	ENST00000617965.2	n.293C>T		non_coding_transcript_exon_variant	Exon 2 of 17	5

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3743 AN: 152106 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00655

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0328

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0371 AC: 9328 AN: 251388 Hom.: 287 AF XY: 0.0348 AC XY: 4723 AN XY: 135864

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0113

Gnomad SAS exome AF: 0.0435

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0291 AC: 42533 AN: 1461668 Hom.: 849 Cov.: 32 AF XY: 0.0290 AC XY: 21072 AN XY: 727142

Gnomad4 AFR exome AF: 0.00505

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0169

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0333

Gnomad4 NFE exome AF: 0.0270

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0246 AC: 3747 AN: 152224 Hom.: 84 Cov.: 32 AF XY: 0.0259 AC XY: 1930 AN XY: 74448

Gnomad4 AFR AF: 0.00653

Gnomad4 AMR AF: 0.0693

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.0412

Gnomad4 FIN AF: 0.0328

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0229 Hom.: 20

Bravo AF: 0.0265

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0243

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn308Asn in exon 7 of JAG1:This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 11% (1274/11536) of Latino chromosomes, including 73 homozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45575136). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 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	-0.57
CADD	Benign	3.1
DANN	Benign	0.88
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: rs45575136; hg19: chr20-10632861;