20-10661481-A-G

Variant names:

• chr20-10661481-A-G
• rs7265068
• NM_000214.3:c.439+2482T>C

Variant summary

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

The NM_000214.3(JAG1):​c.439+2482T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 151,936 control chromosomes in the GnomAD database, including 14,136 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 0.43 (14136 hom., cov: 32)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.439+2482T>C		intron_variant	Intron 3 of 25	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.439+2482T>C		intron_variant	Intron 3 of 25	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.305+721T>C		intron_variant	Intron 1 of 24	2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64974 AN: 151818 Hom.: 14126 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.448

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

GnomAD4 genome AF: 0.428 AC: 65026 AN: 151936 Hom.: 14136 Cov.: 32 AF XY: 0.435 AC XY: 32306 AN XY: 74242

African (AFR) AF: 0.360 AC: 14927 AN: 41416

American (AMR) AF: 0.510 AC: 7797 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1490 AN: 3472

East Asian (EAS) AF: 0.679 AC: 3494 AN: 5148

South Asian (SAS) AF: 0.505 AC: 2425 AN: 4804

European-Finnish (FIN) AF: 0.481 AC: 5079 AN: 10560

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28321 AN: 67944

Other (OTH) AF: 0.450 AC: 950 AN: 2112

Alfa AF: 0.428 Hom.: 2408

Bravo AF: 0.425

Asia WGS AF: 0.585 AC: 2036 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.67
PhyloP100		-0.025
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: rs7265068; hg19: chr20-10642129;