rs2273061

Variant names:

• chr20-10658895-G-A
• rs2273061
• NM_000214.3:c.440-173C>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.440-173C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 152,094 control chromosomes in the GnomAD database, including 16,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.46 (16118 hom., cov: 33)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.91
• Publications: 52 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=-0.94).
• BP6: Variant 20-10658895-G-A is Benign according to our data. Variant chr20-10658895-G-A is described in ClinVar as Benign. ClinVar VariationId is 536536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.65 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.440-173C>T		intron	N/A	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.440-173C>T		intron	N/A	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.440-173C>T		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.440-173C>T		intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69674 AN: 151976 Hom.: 16081 Cov.: 33

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.464

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.459 AC: 69770 AN: 152094 Hom.: 16118 Cov.: 33 AF XY: 0.465 AC XY: 34544 AN XY: 74348

African (AFR) AF: 0.467 AC: 19387 AN: 41490

American (AMR) AF: 0.520 AC: 7938 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1539 AN: 3470

East Asian (EAS) AF: 0.669 AC: 3464 AN: 5178

South Asian (SAS) AF: 0.519 AC: 2496 AN: 4812

European-Finnish (FIN) AF: 0.482 AC: 5092 AN: 10572

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28324 AN: 67980

Other (OTH) AF: 0.465 AC: 983 AN: 2114

Alfa AF: 0.431 Hom.: 66367

Bravo AF: 0.460

Asia WGS AF: 0.600 AC: 2087 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alagille syndrome due to a JAG1 point mutation (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.021
DANN	Benign	0.35
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2273061; hg19: chr20-10639543;