chr20-10649224-T-G

Variant names:

• chr20-10649224-T-G
• rs6108653
• NM_000214.3:c.1349-117A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.1349-117A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 766,934 control chromosomes in the GnomAD database, including 4,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2155 hom., cov: 33)
  • Exomes 𝑓: 0.079 (2640 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.93
• Publications: 8 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 20-10649224-T-G is Benign according to our data. Variant chr20-10649224-T-G is described in ClinVar as Benign. ClinVar VariationId is 1253419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.1349-117A>C		intron_variant	Intron 10 of 25	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.1349-117A>C		intron_variant	Intron 10 of 25	1	NM_000214.3	ENSP00000254958.4

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20352 AN: 152096 Hom.: 2152 Cov.: 33

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0792

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0479

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.116

GnomAD4 exome AF: 0.0789 AC: 48477 AN: 614722 Hom.: 2640 AF XY: 0.0812 AC XY: 26626 AN XY: 327950

African (AFR) AF: 0.287 AC: 4571 AN: 15900

American (AMR) AF: 0.0445 AC: 1414 AN: 31802

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 354 AN: 19342

East Asian (EAS) AF: 0.0394 AC: 1275 AN: 32384

South Asian (SAS) AF: 0.155 AC: 9305 AN: 59892

European-Finnish (FIN) AF: 0.0695 AC: 3257 AN: 46836

Middle Eastern (MID) AF: 0.0510 AC: 153 AN: 3000

European-Non Finnish (NFE) AF: 0.0686 AC: 25609 AN: 373570

Other (OTH) AF: 0.0794 AC: 2539 AN: 31996

GnomAD4 genome AF: 0.134 AC: 20364 AN: 152212 Hom.: 2155 Cov.: 33 AF XY: 0.132 AC XY: 9856 AN XY: 74442

African (AFR) AF: 0.294 AC: 12183 AN: 41482

American (AMR) AF: 0.0791 AC: 1210 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.0476 AC: 247 AN: 5190

South Asian (SAS) AF: 0.160 AC: 772 AN: 4818

European-Finnish (FIN) AF: 0.0649 AC: 689 AN: 10620

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0712 AC: 4845 AN: 68012

Other (OTH) AF: 0.117 AC: 247 AN: 2114

Alfa AF: 0.0863 Hom.: 505

Bravo AF: 0.137

Asia WGS AF: 0.120 AC: 417 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.63
PhyloP100		1.9
Mutation Taster		=99/1	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: rs6108653; hg19: chr20-10629872;