20-10643748-T-C

Variant names:

• chr20-10643748-T-C
• rs2273059
• NM_000214.3:c.2458+30A>G

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.2458+30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,584,856 control chromosomes in the GnomAD database, including 682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (93 hom., cov: 32)
  • Exomes 𝑓: 0.022 (589 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.26
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-10643748-T-C is Benign according to our data. Variant chr20-10643748-T-C is described in ClinVar as Benign. ClinVar VariationId is 255551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0844 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.2458+30A>G		intron	N/A	NP_000205.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.2458+30A>G		intron	N/A	ENSP00000254958.4
	JAG1	ENST00000901230.1		c.2458+30A>G		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.2458+30A>G		intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3273 AN: 152154 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00541

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.0306 AC: 7644 AN: 249526 AF XY: 0.0276

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00458

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0219 AC: 31325 AN: 1432584 Hom.: 589 Cov.: 28 AF XY: 0.0215 AC XY: 15373 AN XY: 714566

African (AFR) AF: 0.00377 AC: 124 AN: 32850

American (AMR) AF: 0.108 AC: 4797 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 60 AN: 25926

East Asian (EAS) AF: 0.00571 AC: 226 AN: 39550

South Asian (SAS) AF: 0.0288 AC: 2463 AN: 85498

European-Finnish (FIN) AF: 0.0221 AC: 1176 AN: 53332

Middle Eastern (MID) AF: 0.0114 AC: 65 AN: 5716

European-Non Finnish (NFE) AF: 0.0195 AC: 21142 AN: 1085700

Other (OTH) AF: 0.0214 AC: 1272 AN: 59490

GnomAD4 genome AF: 0.0215 AC: 3281 AN: 152272 Hom.: 93 Cov.: 32 AF XY: 0.0232 AC XY: 1729 AN XY: 74472

African (AFR) AF: 0.00443 AC: 184 AN: 41566

American (AMR) AF: 0.0884 AC: 1351 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00561 AC: 29 AN: 5166

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4822

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1277 AN: 68022

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.00979 Hom.: 1

Bravo AF: 0.0251

Asia WGS AF: 0.0270 AC: 92 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.069
DANN	Benign	0.41
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2273059; hg19: chr20-10624396;