rs80338240

chr20-10649118-A-Cchr20-10649118-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000214.3(JAG1):c.1349-11T>G variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000919 in 1,584,024 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00094 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (15 hom.)
• Consequence: JAG1 NM_000214.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9620
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.92

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 20-10649118-A-C is Benign according to our data. Variant chr20-10649118-A-C is described in ClinVar as [Benign]. Clinvar id is 255547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000939 (143/152352) while in subpopulation EAS AF= 0.0116 (60/5186). AF 95% confidence interval is 0.00923. There are 3 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.1349-11T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.1349-11T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000214.3	P1

Frequencies

GnomAD3 genomes AF: 0.000939 AC: 143 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00153 AC: 384 AN: 250184 Hom.: 3 AF XY: 0.00153 AC XY: 208 AN XY: 135510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000916 AC: 1312 AN: 1431672 Hom.: 15 Cov.: 27 AF XY: 0.000896 AC XY: 640 AN XY: 714350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.0201

Gnomad4 SAS exome AF: 0.0000819

Gnomad4 FIN exome AF: 0.00603

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.00121 AC XY: 90 AN XY: 74504

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00602

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000514

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Alagille syndrome due to a JAG1 point mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.72
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

Publications

LitVar

Other links and lift over

dbSNP: rs80338240; hg19: chr20-10629766;