chr20-10652213-G-A

Variant names:

• chr20-10652213-G-A
• rs45575136
• NM_000214.3:c.924C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000214.3(JAG1):​c.924C>T​(p.Asn308Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,613,892 control chromosomes in the GnomAD database, including 933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (84 hom., cov: 32)
  • Exomes 𝑓: 0.029 (849 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0580
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 20-10652213-G-A is Benign according to our data. Variant chr20-10652213-G-A is described in ClinVar as Benign. ClinVar VariationId is 42483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.058 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0658 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.924C>T	p.Asn308Asn	synonymous	Exon 7 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.924C>T	p.Asn308Asn	synonymous	Exon 7 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.924C>T	p.Asn308Asn	synonymous	Exon 8 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.924C>T	p.Asn308Asn	synonymous	Exon 7 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3743 AN: 152106 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00655

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0328

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0371 AC: 9328 AN: 251388 AF XY: 0.0348

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0291 AC: 42533 AN: 1461668 Hom.: 849 Cov.: 32 AF XY: 0.0290 AC XY: 21072 AN XY: 727142

African (AFR) AF: 0.00505 AC: 169 AN: 33476

American (AMR) AF: 0.104 AC: 4652 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26134

East Asian (EAS) AF: 0.0169 AC: 671 AN: 39700

South Asian (SAS) AF: 0.0422 AC: 3636 AN: 86256

European-Finnish (FIN) AF: 0.0333 AC: 1780 AN: 53408

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.0270 AC: 30014 AN: 1111822

Other (OTH) AF: 0.0250 AC: 1507 AN: 60382

GnomAD4 genome AF: 0.0246 AC: 3747 AN: 152224 Hom.: 84 Cov.: 32 AF XY: 0.0259 AC XY: 1930 AN XY: 74448

African (AFR) AF: 0.00653 AC: 271 AN: 41524

American (AMR) AF: 0.0693 AC: 1059 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5180

South Asian (SAS) AF: 0.0412 AC: 199 AN: 4828

European-Finnish (FIN) AF: 0.0328 AC: 348 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0254 AC: 1731 AN: 68022

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0229 Hom.: 20

Bravo AF: 0.0265

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0243

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Alagille syndrome due to a JAG1 point mutation (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Isolated Nonsyndromic Congenital Heart Disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.1
DANN	Benign	0.88
PhyloP100		0.058
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs45575136; hg19: chr20-10632861; COSMIC: COSV107294903; COSMIC: COSV107294903;