rs8708

Variant names:

• chr20-10637926-T-C
• rs8708
• NM_000214.3:c.*1572A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.*1572A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,542 control chromosomes in the GnomAD database, including 23,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23632 hom., cov: 33)
  • Exomes 𝑓: 0.56 (64 hom.)
• Consequence: JAG1 NM_000214.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.16
• Publications: 24 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 20-10637926-T-C is Benign according to our data. Variant chr20-10637926-T-C is described in ClinVar as Benign. ClinVar VariationId is 337715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

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.*1572A>G		3_prime_UTR	Exon 26 of 26	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.*1572A>G		3_prime_UTR	Exon 26 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000913736.1		c.*1572A>G		3_prime_UTR	Exon 25 of 25	ENSP00000583795.1
	JAG1	ENST00000913737.1		c.*1572A>G		3_prime_UTR	Exon 25 of 25	ENSP00000583796.1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83738 AN: 152006 Hom.: 23597 Cov.: 33

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.551

GnomAD4 exome AF: 0.557 AC: 233 AN: 418 Hom.: 64 Cov.: 0 AF XY: 0.528 AC XY: 132 AN XY: 250

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.561 AC: 230 AN: 410

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.333 AC: 2 AN: 6

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.551 AC: 83829 AN: 152124 Hom.: 23632 Cov.: 33 AF XY: 0.547 AC XY: 40692 AN XY: 74344

African (AFR) AF: 0.535 AC: 22200 AN: 41492

American (AMR) AF: 0.584 AC: 8927 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1514 AN: 3464

East Asian (EAS) AF: 0.213 AC: 1105 AN: 5178

South Asian (SAS) AF: 0.516 AC: 2488 AN: 4818

European-Finnish (FIN) AF: 0.545 AC: 5759 AN: 10574

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39851 AN: 67992

Other (OTH) AF: 0.553 AC: 1167 AN: 2112

Alfa AF: 0.564 Hom.: 45182

Bravo AF: 0.545

Asia WGS AF: 0.392 AC: 1365 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Isolated Nonsyndromic Congenital Heart Disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.22
DANN	Benign	0.21
PhyloP100		-2.2
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: rs8708; hg19: chr20-10618574; COSMIC: COSV54756127; COSMIC: COSV54756127;