rs114048678

Positions:

• chr20-10672818-C-A
• chr20-10672818-C-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.270G>T​(p.Gly90=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,613,066 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (118 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (105 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.05

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 20-10672818-C-A is Benign according to our data. Variant chr20-10672818-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 42477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10672818-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.270G>T	p.Gly90=	synonymous_variant	2/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.270G>T	p.Gly90=	synonymous_variant	2/26	1	NM_000214.3	P1
	ENST00000667822.1	n.124C>A		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3484 AN: 152158 Hom.: 118 Cov.: 33

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00622 AC: 1557 AN: 250126 Hom.: 53 AF XY: 0.00461 AC XY: 625 AN XY: 135704

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.000799

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00245 AC: 3583 AN: 1460792 Hom.: 105 Cov.: 33 AF XY: 0.00219 AC XY: 1590 AN XY: 726716

Gnomad4 AFR exome AF: 0.0807

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.0229 AC: 3493 AN: 152274 Hom.: 118 Cov.: 33 AF XY: 0.0224 AC XY: 1665 AN XY: 74470

Gnomad4 AFR AF: 0.0784

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0122 Hom.: 19

Bravo AF: 0.0252

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 09, 2011	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2016	- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Alagille syndrome due to a JAG1 point mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.3
DANN	Benign	0.86

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: rs114048678; hg19: chr20-10653466;