20-10642618-T-G

Position:

• chr20-10642618-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000214.3(JAG1):​c.2459-17A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00832 in 1,476,638 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (53 hom.)
• Consequence: JAG1 NM_000214.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.489

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-10642618-T-G is Benign according to our data. Variant chr20-10642618-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 255552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10642618-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00619 (942/152282) while in subpopulation AMR AF= 0.01 (153/15304). AF 95% confidence interval is 0.0088. There are 7 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 942 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.2459-17A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.2459-17A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.2325-17A>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
JAG1	ENST00000617965.2	n.3048-17A>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 942 AN: 152164 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00687 AC: 1724 AN: 250870 Hom.: 11 AF XY: 0.00707 AC XY: 959 AN XY: 135614

Gnomad AFR exome AF: 0.00216

Gnomad AMR exome AF: 0.00524

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00972

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00856 AC: 11343 AN: 1324356 Hom.: 53 Cov.: 21 AF XY: 0.00835 AC XY: 5563 AN XY: 666242

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00563

Gnomad4 ASJ exome AF: 0.000949

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.00969

Gnomad4 OTH exome AF: 0.00834

GnomAD4 genome AF: 0.00619 AC: 942 AN: 152282 Hom.: 7 Cov.: 33 AF XY: 0.00588 AC XY: 438 AN XY: 74446

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00941

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00649 Hom.: 0

Bravo AF: 0.00648

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Alagille syndrome due to a JAG1 point mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Tetralogy of Fallot;C1866053:Deafness, congenital heart defects, and posterior embryotoxon;C1956125:Alagille syndrome due to a JAG1 point mutation;C5562003:Charcot-Marie-Tooth disease, axonal, Type 2HH Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs35891274; hg19: chr20-10623266;