rs1131695

chr20-10652589-G-Achr20-10652589-G-Cchr20-10652589-G-T

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.765C>T(p.Tyr255=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,802 control chromosomes in the GnomAD database, including 168,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14538 hom., cov: 31)
  • Exomes 𝑓: 0.46 (153603 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.608

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=-0.72).
• BP6: Variant 20-10652589-G-A is Benign according to our data. Variant chr20-10652589-G-A is described in ClinVar as [Benign]. Clinvar id is 143063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10652589-G-A is described in Lovd as [Benign]. Variant chr20-10652589-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.608 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.765C>T	p.Tyr255=	synonymous_variant	6/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.765C>T	p.Tyr255=	synonymous_variant	6/26	1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.631C>T		non_coding_transcript_exon_variant	4/25	2
JAG1	ENST00000617965.2	n.134C>T		non_coding_transcript_exon_variant	1/17	5

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65758 AN: 151850 Hom.: 14527 Cov.: 31

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.467

GnomAD3 exomes AF: 0.456 AC: 114409 AN: 250970 Hom.: 26646 AF XY: 0.465 AC XY: 63116 AN XY: 135668

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.501

Gnomad EAS exome AF: 0.343

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.456 AC: 666247 AN: 1460834 Hom.: 153603 Cov.: 39 AF XY: 0.460 AC XY: 334168 AN XY: 726734

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.444

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.532

Gnomad4 FIN exome AF: 0.448

Gnomad4 NFE exome AF: 0.457

Gnomad4 OTH exome AF: 0.460

GnomAD4 genome AF: 0.433 AC: 65799 AN: 151968 Hom.: 14538 Cov.: 31 AF XY: 0.435 AC XY: 32318 AN XY: 74264

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.458

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.344

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.465

Gnomad4 OTH AF: 0.468

Alfa AF: 0.458 Hom.: 13551

Bravo AF: 0.428

Asia WGS AF: 0.460 AC: 1603 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.474

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Alagille syndrome due to a JAG1 point mutation Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided Benign:2

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Deafness, congenital heart defects, and posterior embryotoxon Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Tetralogy of Fallot Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 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
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.42
Dann	Benign	0.90
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: rs1131695; hg19: chr20-10633237; COSMIC: COSV54759391; COSMIC: COSV54759391;