rs2273060

Positions:

• chr20-10658737-A-G
• chr20-10658737-A-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.440-15T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,612,316 control chromosomes in the GnomAD database, including 138,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14149 hom., cov: 33)
  • Exomes 𝑓: 0.41 (124191 hom.)
• Consequence: JAG1 NM_000214.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.853

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=-0.83).
• BP6: Variant 20-10658737-A-G is Benign according to our data. Variant chr20-10658737-A-G is described in ClinVar as [Benign]. Clinvar id is 213524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10658737-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.440-15T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.440-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.306-15T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65581 AN: 151978 Hom.: 14117 Cov.: 33

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.433

GnomAD3 exomes AF: 0.439 AC: 109961 AN: 250398 Hom.: 24709 AF XY: 0.440 AC XY: 59613 AN XY: 135498

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.435

Gnomad EAS exome AF: 0.433

Gnomad SAS exome AF: 0.511

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.410 AC: 598212 AN: 1460220 Hom.: 124191 Cov.: 38 AF XY: 0.412 AC XY: 299631 AN XY: 726526

Gnomad4 AFR exome AF: 0.467

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.433

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.422

GnomAD4 genome AF: 0.432 AC: 65674 AN: 152096 Hom.: 14149 Cov.: 33 AF XY: 0.433 AC XY: 32201 AN XY: 74344

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.430

Gnomad4 SAS AF: 0.504

Gnomad4 FIN AF: 0.401

Gnomad4 NFE AF: 0.404

Gnomad4 OTH AF: 0.435

Alfa AF: 0.409 Hom.: 14241

Bravo AF: 0.433

Asia WGS AF: 0.512 AC: 1783 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.4
DANN	Benign	0.36

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: rs2273060; hg19: chr20-10639385; COSMIC: COSV54757234;