chr20-10639627-G-A

Variant names:

• chr20-10639627-G-A
• rs1051421
• NM_000214.3:c.3528C>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.3528C>T​(p.Tyr1176Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.253 in 1,614,010 control chromosomes in the GnomAD database, including 53,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4229 hom., cov: 33)
  • Exomes 𝑓: 0.26 (49160 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.44
• Publications: 24 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=-0.58).
• BP6: Variant 20-10639627-G-A is Benign according to our data. Variant chr20-10639627-G-A is described in ClinVar as Benign. ClinVar VariationId is 42478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 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.3528C>T	p.Tyr1176Tyr	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.3528C>T	p.Tyr1176Tyr	synonymous	Exon 26 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.3528C>T	p.Tyr1176Tyr	synonymous	Exon 27 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.3522C>T	p.Tyr1174Tyr	synonymous	Exon 26 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33775 AN: 152058 Hom.: 4232 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.243 AC: 61006 AN: 251472 AF XY: 0.244

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.279

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.256 AC: 373983 AN: 1461834 Hom.: 49160 Cov.: 35 AF XY: 0.256 AC XY: 185971 AN XY: 727220

African (AFR) AF: 0.102 AC: 3401 AN: 33480

American (AMR) AF: 0.273 AC: 12204 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 7732 AN: 26134

East Asian (EAS) AF: 0.173 AC: 6862 AN: 39700

South Asian (SAS) AF: 0.195 AC: 16853 AN: 86256

European-Finnish (FIN) AF: 0.221 AC: 11785 AN: 53414

Middle Eastern (MID) AF: 0.258 AC: 1490 AN: 5766

European-Non Finnish (NFE) AF: 0.269 AC: 298889 AN: 1111966

Other (OTH) AF: 0.245 AC: 14767 AN: 60396

GnomAD4 genome AF: 0.222 AC: 33770 AN: 152176 Hom.: 4229 Cov.: 33 AF XY: 0.220 AC XY: 16333 AN XY: 74402

African (AFR) AF: 0.108 AC: 4495 AN: 41540

American (AMR) AF: 0.284 AC: 4339 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 995 AN: 3470

East Asian (EAS) AF: 0.155 AC: 801 AN: 5184

South Asian (SAS) AF: 0.191 AC: 920 AN: 4824

European-Finnish (FIN) AF: 0.216 AC: 2284 AN: 10592

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18890 AN: 67986

Other (OTH) AF: 0.257 AC: 541 AN: 2108

Alfa AF: 0.265 Hom.: 10902

Bravo AF: 0.221

Asia WGS AF: 0.169 AC: 590 AN: 3478

EpiCase AF: 0.284

EpiControl AF: 0.282

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	not provided (1)
-	-	1	Tetralogy of Fallot (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.8
DANN	Benign	0.95
PhyloP100		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs1051421; hg19: chr20-10620275; COSMIC: COSV54754834; COSMIC: COSV54754834;