20-10639738-A-G

Variant names:

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

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.3417T>C​(p.Tyr1139Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,856 control chromosomes in the GnomAD database, including 342,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39477 hom., cov: 32)
  • Exomes 𝑓: 0.64 (302723 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 20-10639738-A-G is Benign according to our data. Variant chr20-10639738-A-G is described in ClinVar as Benign. ClinVar VariationId is 137595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.893 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.3417T>C	p.Tyr1139Tyr	synonymous	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>C	p.Tyr1139Tyr	synonymous	Exon 26 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.3417T>C	p.Tyr1139Tyr	synonymous	Exon 27 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.3411T>C	p.Tyr1137Tyr	synonymous	Exon 26 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107636 AN: 152002 Hom.: 39419 Cov.: 32

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.707

GnomAD2 exomes AF: 0.651 AC: 163796 AN: 251484 AF XY: 0.653

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.639

GnomAD4 exome AF: 0.640 AC: 935653 AN: 1461736 Hom.: 302723 Cov.: 48 AF XY: 0.643 AC XY: 467708 AN XY: 727188

African (AFR) AF: 0.909 AC: 30427 AN: 33480

American (AMR) AF: 0.639 AC: 28595 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 15828 AN: 26136

East Asian (EAS) AF: 0.428 AC: 17011 AN: 39700

South Asian (SAS) AF: 0.765 AC: 65951 AN: 86258

European-Finnish (FIN) AF: 0.577 AC: 30842 AN: 53416

Middle Eastern (MID) AF: 0.646 AC: 3728 AN: 5768

European-Non Finnish (NFE) AF: 0.634 AC: 704511 AN: 1111868

Other (OTH) AF: 0.642 AC: 38760 AN: 60386

GnomAD4 genome AF: 0.708 AC: 107755 AN: 152120 Hom.: 39477 Cov.: 32 AF XY: 0.705 AC XY: 52450 AN XY: 74354

African (AFR) AF: 0.901 AC: 37405 AN: 41524

American (AMR) AF: 0.684 AC: 10458 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2067 AN: 3468

East Asian (EAS) AF: 0.444 AC: 2288 AN: 5154

South Asian (SAS) AF: 0.765 AC: 3686 AN: 4816

European-Finnish (FIN) AF: 0.569 AC: 6021 AN: 10578

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43440 AN: 67984

Other (OTH) AF: 0.706 AC: 1492 AN: 2112

Alfa AF: 0.663 Hom.: 32042

Bravo AF: 0.716

Asia WGS AF: 0.629 AC: 2189 AN: 3478

EpiCase AF: 0.641

EpiControl AF: 0.643

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	JAG1-related disorder (1)
-	-	1	not provided (1)
-	-	1	Tetralogy of Fallot (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.49
DANN	Benign	0.59
PhyloP100		-0.47
Mutation Taster		=94/6	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: rs1051419; hg19: chr20-10620386; COSMIC: COSV54753151; COSMIC: COSV54753151;