rs6133987

Variant names:

• chr20-10669706-C-T
• rs6133987
• NM_000214.3:c.387+2995G>A

Variant summary

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

The NM_000214.3(JAG1):​c.387+2995G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 151,898 control chromosomes in the GnomAD database, including 2,762 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 0.17 (2762 hom., cov: 31)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 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.387+2995G>A		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.387+2995G>A		intron	N/A	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.387+2995G>A		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.387+2995G>A		intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26134 AN: 151786 Hom.: 2764 Cov.: 31

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.172 AC: 26123 AN: 151898 Hom.: 2762 Cov.: 31 AF XY: 0.168 AC XY: 12439 AN XY: 74218

African (AFR) AF: 0.0607 AC: 2517 AN: 41440

American (AMR) AF: 0.209 AC: 3196 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1018 AN: 3466

East Asian (EAS) AF: 0.129 AC: 667 AN: 5176

South Asian (SAS) AF: 0.118 AC: 565 AN: 4798

European-Finnish (FIN) AF: 0.164 AC: 1726 AN: 10504

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.228 AC: 15523 AN: 67952

Other (OTH) AF: 0.211 AC: 443 AN: 2098

Alfa AF: 0.221 Hom.: 7500

Bravo AF: 0.175

Asia WGS AF: 0.131 AC: 454 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.71
PhyloP100		0.41
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: rs6133987; hg19: chr20-10650354;