NM_000214.3:c.3417T>G

Variant names:

• chr20-10639738-A-C
• rs1051419
• NM_000214.3:c.3417T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000214.3(JAG1):​c.3417T>G​(p.Tyr1139*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y1139Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAG1 NM_000214.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• Publications: 37 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0656 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.3417T>G	p.Tyr1139*	stop_gained	Exon 26 of 26	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.3417T>G	p.Tyr1139*	stop_gained	Exon 26 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.3417T>G	p.Tyr1139*	stop_gained	Exon 27 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.3411T>G	p.Tyr1137*	stop_gained	Exon 26 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.34	N
PhyloP100		-0.47
Vest4		0.92
GERP RS		-1.1
Mutation Taster		=12/188	disease causing

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: rs1051419; hg19: chr20-10620386;