chr20-10664057-G-A

Variant names:

• chr20-10664057-G-A
• rs17536052
• NM_000214.3:c.388-43C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.388-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0681 in 1,547,914 control chromosomes in the GnomAD database, including 4,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (296 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3907 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.826
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-10664057-G-A is Benign according to our data. Variant chr20-10664057-G-A is described in ClinVar as Benign. ClinVar VariationId is 255559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.388-43C>T		intron	N/A	NP_000205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.388-43C>T		intron	N/A	ENSP00000254958.4

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8288 AN: 152094 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0795

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0765

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0628 AC: 15770 AN: 251170 AF XY: 0.0601

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0836

Gnomad NFE exome AF: 0.0754

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0695 AC: 97042 AN: 1395702 Hom.: 3907 Cov.: 23 AF XY: 0.0677 AC XY: 47262 AN XY: 698144

African (AFR) AF: 0.0144 AC: 463 AN: 32176

American (AMR) AF: 0.107 AC: 4787 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 297 AN: 25788

East Asian (EAS) AF: 0.000406 AC: 16 AN: 39376

South Asian (SAS) AF: 0.0297 AC: 2525 AN: 84906

European-Finnish (FIN) AF: 0.0868 AC: 4628 AN: 53332

Middle Eastern (MID) AF: 0.0168 AC: 95 AN: 5642

European-Non Finnish (NFE) AF: 0.0769 AC: 80909 AN: 1051644

Other (OTH) AF: 0.0571 AC: 3322 AN: 58216

GnomAD4 genome AF: 0.0545 AC: 8297 AN: 152212 Hom.: 296 Cov.: 32 AF XY: 0.0537 AC XY: 3995 AN XY: 74420

African (AFR) AF: 0.0176 AC: 730 AN: 41542

American (AMR) AF: 0.0799 AC: 1222 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4816

European-Finnish (FIN) AF: 0.0795 AC: 843 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0765 AC: 5200 AN: 67994

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0567 Hom.: 188

Bravo AF: 0.0528

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.24
DANN	Benign	0.77
PhyloP100		-0.83
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: rs17536052; hg19: chr20-10644705;