20-10641432-CAA-CA

Variant names:

• chr20-10641432-CA-C
• rs3215563
• NM_000214.3:c.2916+27delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.2916+27delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4788 hom., cov: 0)
  • Exomes 𝑓: 0.28 (49714 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.173
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 20-10641432-CA-C is Benign according to our data. Variant chr20-10641432-CA-C is described in ClinVar as Benign. ClinVar VariationId is 255555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2916+27delT		intron_variant	Intron 23 of 25	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2916+27delT		intron_variant	Intron 23 of 25	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.2782+27delT		intron_variant	Intron 21 of 24	2
JAG1	ENST00000617357.1	n.-157delT		upstream_gene_variant		2
JAG1	ENST00000617965.2	n.*147delT		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.234 AC: 34896 AN: 149110 Hom.: 4789 Cov.: 0

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.270

GnomAD4 exome AF: 0.280 AC: 380728 AN: 1360826 Hom.: 49714 Cov.: 13 AF XY: 0.279 AC XY: 189790 AN XY: 679584

African (AFR) AF: 0.0889 AC: 2699 AN: 30374

American (AMR) AF: 0.352 AC: 15272 AN: 43434

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 7780 AN: 24896

East Asian (EAS) AF: 0.181 AC: 6672 AN: 36944

South Asian (SAS) AF: 0.220 AC: 18134 AN: 82320

European-Finnish (FIN) AF: 0.249 AC: 12269 AN: 49270

Middle Eastern (MID) AF: 0.273 AC: 1472 AN: 5386

European-Non Finnish (NFE) AF: 0.292 AC: 301334 AN: 1031754

Other (OTH) AF: 0.267 AC: 15096 AN: 56448

GnomAD4 genome AF: 0.234 AC: 34920 AN: 149210 Hom.: 4788 Cov.: 0 AF XY: 0.234 AC XY: 16999 AN XY: 72772

African (AFR) AF: 0.0885 AC: 3568 AN: 40330

American (AMR) AF: 0.349 AC: 5252 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1025 AN: 3452

East Asian (EAS) AF: 0.159 AC: 804 AN: 5064

South Asian (SAS) AF: 0.208 AC: 979 AN: 4710

European-Finnish (FIN) AF: 0.247 AC: 2466 AN: 9974

Middle Eastern (MID) AF: 0.252 AC: 73 AN: 290

European-Non Finnish (NFE) AF: 0.294 AC: 19777 AN: 67350

Other (OTH) AF: 0.271 AC: 562 AN: 2072

Alfa AF: 0.212 Hom.: 552

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Deafness, congenital heart defects, and posterior embryotoxon Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alagille syndrome due to a JAG1 point mutation Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tetralogy of Fallot Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
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: rs3215563; hg19: chr20-10622080;