20-10659340-T-C

Variant names:

• chr20-10659340-T-C
• rs3790160
• NM_000214.3:c.440-618A>G

Variant summary

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

The NM_000214.3(JAG1):​c.440-618A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 152,160 control chromosomes in the GnomAD database, including 22,582 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 0.54 (22582 hom., cov: 34)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.148
• Publications: 29 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.440-618A>G		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.440-618A>G		intron_variant	Intron 3 of 25	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.306-618A>G		intron_variant	Intron 1 of 24	2

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82503 AN: 152042 Hom.: 22535 Cov.: 34

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.692

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.554

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

GnomAD4 genome AF: 0.543 AC: 82607 AN: 152160 Hom.: 22582 Cov.: 34 AF XY: 0.551 AC XY: 40989 AN XY: 74392

African (AFR) AF: 0.572 AC: 23733 AN: 41506

American (AMR) AF: 0.582 AC: 8902 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1722 AN: 3470

East Asian (EAS) AF: 0.711 AC: 3678 AN: 5170

South Asian (SAS) AF: 0.692 AC: 3336 AN: 4822

European-Finnish (FIN) AF: 0.556 AC: 5876 AN: 10574

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33556 AN: 67996

Other (OTH) AF: 0.557 AC: 1179 AN: 2116

Alfa AF: 0.512 Hom.: 50697

Bravo AF: 0.540

Asia WGS AF: 0.698 AC: 2428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.8
DANN	Benign	0.80
PhyloP100		-0.15
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: rs3790160; hg19: chr20-10639988;