rs6133986

Variant names:

• chr20-10665125-G-A
• rs6133986
• NM_000214.3:c.388-1111C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000214.3(JAG1):​c.388-1111C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 152,118 control chromosomes in the GnomAD database, including 852 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (852 hom., cov: 33)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.222
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 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.388-1111C>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.388-1111C>T		intron	N/A	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.388-1111C>T		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.388-1111C>T		intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15418 AN: 152000 Hom.: 852 Cov.: 33

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.110

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

GnomAD4 genome AF: 0.101 AC: 15427 AN: 152118 Hom.: 852 Cov.: 33 AF XY: 0.102 AC XY: 7561 AN XY: 74392

African (AFR) AF: 0.0863 AC: 3577 AN: 41460

American (AMR) AF: 0.0829 AC: 1267 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3468

East Asian (EAS) AF: 0.0247 AC: 128 AN: 5186

South Asian (SAS) AF: 0.121 AC: 585 AN: 4824

European-Finnish (FIN) AF: 0.100 AC: 1059 AN: 10580

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8067 AN: 67996

Other (OTH) AF: 0.111 AC: 234 AN: 2108

Alfa AF: 0.111 Hom.: 1466

Bravo AF: 0.0986

Asia WGS AF: 0.0670 AC: 233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		-0.22
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: rs6133986; hg19: chr20-10645773;