rs146144464

Variant names:

• chr20-10638879-G-A
• rs146144464
• NM_000214.3:c.*619C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BS1 BS2

The NM_000214.3(JAG1):​c.*619C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00469 in 153,800 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (0 hom.)
• Consequence: JAG1 NM_000214.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.97
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).
• BP6: Variant 20-10638879-G-A is Benign according to our data. Variant chr20-10638879-G-A is described in ClinVar as [Benign]. Clinvar id is 337733.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00463 (705/152140) while in subpopulation NFE AF = 0.00763 (519/68008). AF 95% confidence interval is 0.00709. There are 1 homozygotes in GnomAd4. There are 326 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 705 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.*619C>T		3_prime_UTR_variant	Exon 26 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.*619C>T		3_prime_UTR_variant	Exon 26 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.3549+593C>T		intron_variant	Intron 24 of 24	2

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 705 AN: 152022 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00763

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.00964 AC: 16 AN: 1660 Hom.: 0 Cov.: 0 AF XY: 0.0125 AC XY: 11 AN XY: 882

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 18

South Asian (SAS) AF: 0.00 AC: 0 AN: 94

European-Finnish (FIN) AF: 0.0164 AC: 7 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0108 AC: 9 AN: 832

Other (OTH) AF: 0.00 AC: 0 AN: 32

GnomAD4 genome AF: 0.00463 AC: 705 AN: 152140 Hom.: 1 Cov.: 33 AF XY: 0.00438 AC XY: 326 AN XY: 74368

African (AFR) AF: 0.00118 AC: 49 AN: 41502

American (AMR) AF: 0.00144 AC: 22 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00763 AC: 519 AN: 68008

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00704 Hom.: 1

Bravo AF: 0.00386

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.90
PhyloP100		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=98/2	polymorphism

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: rs146144464; hg19: chr20-10619527;