NM_000214.3:c.765C>T

Variant names:

• chr20-10652589-G-A
• rs1131695
• NM_000214.3:c.765C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000214.3(JAG1):​c.765C>T​(p.Tyr255Tyr) 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:14
• Conservation: PhyloP100: -0.608
• Publications: 28 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Charcot-Marie-Tooth disease, axonal, Type 2HH

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 143063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.765C>T	p.Tyr255Tyr	synonymous	Exon 6 of 26	NP_000205.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.765C>T	p.Tyr255Tyr	synonymous	Exon 6 of 26	ENSP00000254958.4
	JAG1	ENST00000901230.1		c.765C>T	p.Tyr255Tyr	synonymous	Exon 7 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.765C>T	p.Tyr255Tyr	synonymous	Exon 6 of 26	ENSP00000583797.1

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

GnomAD2 exomes AF: 0.456 AC: 114409 AN: 250970 AF XY: 0.465

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 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

African (AFR) AF: 0.357 AC: 11941 AN: 33472

American (AMR) AF: 0.444 AC: 19845 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12934 AN: 26118

East Asian (EAS) AF: 0.326 AC: 12936 AN: 39668

South Asian (SAS) AF: 0.532 AC: 45855 AN: 86224

European-Finnish (FIN) AF: 0.448 AC: 23895 AN: 53304

Middle Eastern (MID) AF: 0.561 AC: 3230 AN: 5756

European-Non Finnish (NFE) AF: 0.457 AC: 507854 AN: 1111256

Other (OTH) AF: 0.460 AC: 27757 AN: 60354

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

African (AFR) AF: 0.354 AC: 14674 AN: 41434

American (AMR) AF: 0.458 AC: 7000 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1747 AN: 3472

East Asian (EAS) AF: 0.344 AC: 1768 AN: 5146

South Asian (SAS) AF: 0.533 AC: 2574 AN: 4832

European-Finnish (FIN) AF: 0.451 AC: 4749 AN: 10530

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31597 AN: 67984

Other (OTH) AF: 0.468 AC: 979 AN: 2092

Alfa AF: 0.454 Hom.: 20563

Bravo AF: 0.428

Asia WGS AF: 0.460 AC: 1603 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Alagille syndrome due to a JAG1 point mutation (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Deafness, congenital heart defects, and posterior embryotoxon (1)
-	-	1	Isolated Nonsyndromic Congenital Heart Disease (1)
-	-	1	Tetralogy of Fallot (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.42
DANN	Benign	0.90
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs1131695; hg19: chr20-10633237; COSMIC: COSV54759391; COSMIC: COSV54759391;