chr20-10645156-T-G

Variant names:

• chr20-10645156-T-G
• rs1801140
• NM_000214.3:c.2214A>C

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.2214A>C​(p.Thr738Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,222 control chromosomes in the GnomAD database, including 9,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (698 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8696 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.89
• Publications: 20 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=-0.86).
• BP6: Variant 20-10645156-T-G is Benign according to our data. Variant chr20-10645156-T-G is described in ClinVar as Benign. ClinVar VariationId is 42473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 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.2214A>C	p.Thr738Thr	synonymous	Exon 17 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.2214A>C	p.Thr738Thr	synonymous	Exon 17 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.2214A>C	p.Thr738Thr	synonymous	Exon 18 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.2214A>C	p.Thr738Thr	synonymous	Exon 17 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13368 AN: 152126 Hom.: 698 Cov.: 33

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.0971

GnomAD2 exomes AF: 0.111 AC: 27930 AN: 251464 AF XY: 0.115

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.0793

Gnomad EAS exome AF: 0.0456

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0985

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.103 AC: 150737 AN: 1460978 Hom.: 8696 Cov.: 31 AF XY: 0.106 AC XY: 76954 AN XY: 726836

African (AFR) AF: 0.0335 AC: 1121 AN: 33476

American (AMR) AF: 0.139 AC: 6233 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0799 AC: 2089 AN: 26136

East Asian (EAS) AF: 0.0427 AC: 1693 AN: 39694

South Asian (SAS) AF: 0.205 AC: 17712 AN: 86230

European-Finnish (FIN) AF: 0.119 AC: 6349 AN: 53418

Middle Eastern (MID) AF: 0.107 AC: 619 AN: 5764

European-Non Finnish (NFE) AF: 0.0981 AC: 108955 AN: 1111178

Other (OTH) AF: 0.0988 AC: 5966 AN: 60358

GnomAD4 genome AF: 0.0880 AC: 13400 AN: 152244 Hom.: 698 Cov.: 33 AF XY: 0.0909 AC XY: 6768 AN XY: 74436

African (AFR) AF: 0.0355 AC: 1477 AN: 41558

American (AMR) AF: 0.141 AC: 2155 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 284 AN: 3470

East Asian (EAS) AF: 0.0451 AC: 234 AN: 5184

South Asian (SAS) AF: 0.191 AC: 922 AN: 4820

European-Finnish (FIN) AF: 0.119 AC: 1263 AN: 10612

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0989 AC: 6730 AN: 68018

Other (OTH) AF: 0.101 AC: 213 AN: 2112

Alfa AF: 0.0888 Hom.: 526

Bravo AF: 0.0833

Asia WGS AF: 0.153 AC: 533 AN: 3478

EpiCase AF: 0.0992

EpiControl AF: 0.0952

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.86
CADD	Benign	0.20
DANN	Benign	0.44
PhyloP100		-1.9
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: rs1801140; hg19: chr20-10625804; COSMIC: COSV105039752; COSMIC: COSV105039752;