rs3215563

Variant names:

• chr20-10641432-CAA-C
• rs3215563
• NM_000214.3:c.2916+26_2916+27delTT

Your query was ambiguous. Multiple possible variants found:

• chr20-10641432-CAA-C
• chr20-10641432-CAA-CA
• chr20-10641432-CAA-CAAA
• chr20-10641432-CAA-CAAAA
• chr20-10641432-CAA-CAAAAA
• chr20-10641432-CAA-CAAAAAAAAAAAAAAACAAAAAACAAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000214.3(JAG1):​c.2916+26_2916+27delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 1,363,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000066 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2916+26_2916+27delTT		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+26_2916+27delTT		intron_variant	Intron 23 of 25	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.2782+26_2782+27delTT		intron_variant	Intron 21 of 24	2
JAG1	ENST00000617357.1	n.-158_-157delTT		upstream_gene_variant		2
JAG1	ENST00000617965.2	n.*146_*147delTT		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149164 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000660 AC: 9 AN: 1363742 Hom.: 0 AF XY: 0.00000734 AC XY: 5 AN XY: 680976

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30468

American (AMR) AF: 0.00 AC: 0 AN: 43460

Ashkenazi Jewish (ASJ) AF: 0.0000401 AC: 1 AN: 24924

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 36986

South Asian (SAS) AF: 0.00 AC: 0 AN: 82506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5394

European-Non Finnish (NFE) AF: 0.00000580 AC: 6 AN: 1034044

Other (OTH) AF: 0.0000177 AC: 1 AN: 56570

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00398175), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 149164 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72694

African (AFR) AF: 0.00 AC: 0 AN: 40230

American (AMR) AF: 0.00 AC: 0 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67374

Other (OTH) AF: 0.00 AC: 0 AN: 2050

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.073
Mutation Taster		=100/0	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: rs3215563; hg19: chr20-10622080;