NM_000214.3:c.*756A>G

Variant names:

• chr20-10638742-T-C
• rs45534738
• NM_000214.3:c.*756A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000214.3(JAG1):​c.*756A>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 0.00622 in 152,716 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (0 hom.)
• Consequence: JAG1 NM_000214.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.27
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 20-10638742-T-C is Benign according to our data. Variant chr20-10638742-T-C is described in ClinVar as Benign. ClinVar VariationId is 337730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00623 (948/152286) while in subpopulation NFE AF = 0.0107 (725/68022). AF 95% confidence interval is 0.01. There are 2 homozygotes in GnomAd4. There are 407 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 948 AD gene.

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.*756A>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.*756A>G		3_prime_UTR	Exon 26 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000913738.1		c.*756A>G		3_prime_UTR	Exon 26 of 26	ENSP00000583797.1
	JAG1	ENST00000913736.1		c.*756A>G		3_prime_UTR	Exon 25 of 25	ENSP00000583795.1

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 948 AN: 152168 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00465 AC: 2 AN: 430 Hom.: 0 Cov.: 0 AF XY: 0.00775 AC XY: 2 AN XY: 258

African (AFR) AF: 0.00 AC: 0 AN: 2

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: 0.00478 AC: 2 AN: 418

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00623 AC: 948 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00547 AC XY: 407 AN XY: 74466

African (AFR) AF: 0.00207 AC: 86 AN: 41566

American (AMR) AF: 0.00386 AC: 59 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00866 AC: 30 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 725 AN: 68022

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00564 Hom.: 0

Bravo AF: 0.00630

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs45534738; hg19: chr20-10619390;