chr20-10672818-C-A

Variant names:

• chr20-10672818-C-A
• rs114048678
• NM_000214.3:c.270G>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.270G>T​(p.Gly90Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,613,066 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (118 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (105 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.05
• Publications: 3 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]

LINC01752 (HGNC:52540): (long intergenic non-protein coding RNA 1752)

ENSG00000270792 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 20-10672818-C-A is Benign according to our data. Variant chr20-10672818-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.270G>T	p.Gly90Gly	synonymous	Exon 2 of 26	NP_000205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.270G>T	p.Gly90Gly	synonymous	Exon 2 of 26	ENSP00000254958.4
	LINC01752	ENST00000667822.1		n.124C>A		non_coding_transcript_exon	Exon 1 of 2
	LINC01752	ENST00000716704.1		n.106C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3484 AN: 152158 Hom.: 118 Cov.: 33

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00622 AC: 1557 AN: 250126 AF XY: 0.00461

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.000799

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00245 AC: 3583 AN: 1460792 Hom.: 105 Cov.: 33 AF XY: 0.00219 AC XY: 1590 AN XY: 726716

African (AFR) AF: 0.0807 AC: 2700 AN: 33474

American (AMR) AF: 0.00456 AC: 204 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.00151 AC: 79 AN: 52396

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000145 AC: 161 AN: 1111952

Other (OTH) AF: 0.00586 AC: 354 AN: 60386

GnomAD4 genome AF: 0.0229 AC: 3493 AN: 152274 Hom.: 118 Cov.: 33 AF XY: 0.0224 AC XY: 1665 AN XY: 74470

African (AFR) AF: 0.0784 AC: 3257 AN: 41544

American (AMR) AF: 0.00889 AC: 136 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68032

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0129 Hom.: 22

Bravo AF: 0.0252

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Alagille syndrome due to a JAG1 point mutation (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	1.3
DANN	Benign	0.86
PhyloP100		-1.1
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: rs114048678; hg19: chr20-10653466;