20-10641432-CAA-CAAAAA

Variant names:

• chr20-10641432-C-CAAA
• rs3215563
• NM_000214.3:c.2916+25_2916+27dupTTT

Variant summary

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

The NM_000214.3(JAG1):​c.2916+25_2916+27dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. 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: not found (cov: 0)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.173
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.2916+25_2916+27dupTTT		intron	N/A	NP_000205.1	P78504-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.2916+27_2916+28insTTT		intron	N/A	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.2916+27_2916+28insTTT		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.2910+27_2910+28insTTT		intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000733 AC: 10 AN: 1363638 Hom.: 0 Cov.: 13 AF XY: 0.00000294 AC XY: 2 AN XY: 680936

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

African (AFR) AF: 0.0000328 AC: 1 AN: 30464

American (AMR) AF: 0.00 AC: 0 AN: 43462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24924

East Asian (EAS) AF: 0.00 AC: 0 AN: 36986

South Asian (SAS) AF: 0.00 AC: 0 AN: 82494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49388

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

European-Non Finnish (NFE) AF: 0.00000870 AC: 9 AN: 1033958

Other (OTH) AF: 0.00 AC: 0 AN: 56568

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3215563; hg19: chr20-10622080;