rs2273061

Variant names:

• chr20-10658895-G-A
• rs2273061
• NM_000214.3:c.440-173C>T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.440-173C>T		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.440-173C>T		intron_variant	Intron 3 of 25	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.306-173C>T		intron_variant	Intron 1 of 24	2

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

Gnomad4 AFR AF: 0.467

Gnomad4 AMR AF: 0.520

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.669

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.482

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.465

Alfa AF: 0.427 Hom.: 29703

Bravo AF: 0.460

Asia WGS AF: 0.600 AC: 2087 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20096396) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.021
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs2273061; hg19: chr20-10639543;