rs2273060

Variant names:

• chr20-10658737-A-G
• rs2273060
• NM_000214.3:c.440-15T>C

Your query was ambiguous. Multiple possible variants found:

• chr20-10658737-A-G
• chr20-10658737-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.440-15T>C variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.853
• Publications: 14 publications found

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]

JAG1 Gene-Disease associations (from GenCC):

• Alagille syndrome due to a JAG1 point mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 213524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.440-15T>C		intron	N/A	NP_000205.1	P78504-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.440-15T>C		intron	N/A	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.440-15T>C		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.440-15T>C		intron	N/A	ENSP00000583797.1

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

GnomAD2 exomes AF: 0.439 AC: 109961 AN: 250398 AF XY: 0.440

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 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

African (AFR) AF: 0.467 AC: 15613 AN: 33442

American (AMR) AF: 0.502 AC: 22448 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 11354 AN: 26118

East Asian (EAS) AF: 0.433 AC: 17207 AN: 39700

South Asian (SAS) AF: 0.505 AC: 43526 AN: 86216

European-Finnish (FIN) AF: 0.402 AC: 21485 AN: 53396

Middle Eastern (MID) AF: 0.488 AC: 2787 AN: 5706

European-Non Finnish (NFE) AF: 0.395 AC: 438350 AN: 1110580

Other (OTH) AF: 0.422 AC: 25442 AN: 60338

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

African (AFR) AF: 0.461 AC: 19140 AN: 41508

American (AMR) AF: 0.473 AC: 7222 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1539 AN: 3468

East Asian (EAS) AF: 0.430 AC: 2223 AN: 5166

South Asian (SAS) AF: 0.504 AC: 2429 AN: 4816

European-Finnish (FIN) AF: 0.401 AC: 4244 AN: 10584

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27437 AN: 67964

Other (OTH) AF: 0.435 AC: 916 AN: 2106

Alfa AF: 0.411 Hom.: 16947

Bravo AF: 0.433

Asia WGS AF: 0.512 AC: 1783 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Alagille syndrome due to a JAG1 point mutation (2)
-	-	1	Deafness, congenital heart defects, and posterior embryotoxon (1)
-	-	1	Isolated Nonsyndromic Congenital Heart Disease (1)
-	-	1	not provided (1)
-	-	1	Tetralogy of Fallot (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.4
DANN	Benign	0.36
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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