rs6108652

chr20-10641274-T-C

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.2917-30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,611,374 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (99 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (84 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.38

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=-0.81).
• BP6: Variant 20-10641274-T-C is Benign according to our data. Variant chr20-10641274-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10641274-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.2917-30A>G		intron_variant		ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.2917-30A>G		intron_variant		1	NM_000214.3	P1
JAG1	ENST00000617357.1	n.3A>G		non_coding_transcript_exon_variant	1/2	2
JAG1	ENST00000423891.6	n.2783-30A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3027 AN: 151174 Hom.: 99 Cov.: 33

Gnomad AFR AF: 0.0684

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.0179

GnomAD3 exomes AF: 0.00505 AC: 1251 AN: 247622 Hom.: 37 AF XY: 0.00374 AC XY: 502 AN XY: 134182

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000201

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00200 AC: 2921 AN: 1460082 Hom.: 84 Cov.: 32 AF XY: 0.00171 AC XY: 1239 AN XY: 726490

Gnomad4 AFR exome AF: 0.0671

Gnomad4 AMR exome AF: 0.00492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00511

GnomAD4 genome AF: 0.0200 AC: 3029 AN: 151292 Hom.: 99 Cov.: 33 AF XY: 0.0199 AC XY: 1470 AN XY: 73912

Gnomad4 AFR AF: 0.0682

Gnomad4 AMR AF: 0.00933

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000251

Gnomad4 OTH AF: 0.0177

Alfa AF: 0.00510 Hom.: 17

Bravo AF: 0.0223

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.33
Dann	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6108652; hg19: chr20-10621922;