Variant 4-26319887-A-AG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_005349.4(RBPJ):c.-58+1dupG variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000288 in 1,564,458 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

RBPJ
NM_005349.4 splice_donor, intron

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.12

Variant links:

Genes affected

RBPJ (HGNC:5724): (recombination signal binding protein for immunoglobulin kappa J region) The protein encoded by this gene is a transcriptional regulator important in the Notch signaling pathway. The encoded protein acts as a repressor when not bound to Notch proteins and an activator when bound to Notch proteins. It is thought to function by recruiting chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins to Notch signaling pathway genes. Several transcript variants encoding different isoforms have been found for this gene, and several pseudogenes of this gene exist on chromosome 9. [provided by RefSeq, Oct 2013]

RBPJ links:

RBPJ (HGNC:):

RBPJ links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09447771 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of 0 (no position change), new splice context is: aggGTagga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein	UniProt
RBPJ	NM_001374400.1 linkuse as main transcript	c.-58+119dupG	intron_variant	NP_001361329.1
RBPJ	NM_005349.4 linkuse as main transcript	c.-58+1dupG	splice_donor_variant, intron_variant	NP_005340.2	Q06330-1
RBPJ	NM_001374401.1 linkuse as main transcript	c.-166-42557dupG	intron_variant	NP_001361330.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	Protein	UniProt
RBPJ	ENST00000345843.8 linkuse as main transcript	c.-47+1dupG	splice_donor_variant, intron_variant	1	ENSP00000305815.6	Q06330-5
RBPJ	ENST00000342295.6 linkuse as main transcript	c.-58+1dupG	splice_donor_variant, intron_variant	5	ENSP00000345206.1	Q06330-1
RBPJ	ENST00000512671.6 linkuse as main transcript	c.-58+119dupG	intron_variant	2	ENSP00000423644.2	Q06330-1D6R946

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151342

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

238590

Hom.:

AF XY:

0.0000922

AC XY:

AN XY:

130202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000702

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1413002

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

704794

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000869

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.33e-7

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74048

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.000132

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RBPJ-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2024

The RBPJ c.14+1dupG variant is predicted to result in a duplication affecting a canonical splice site. However, this variant affects an alternatively spliced exon and in the primary transcript (NM_005349.3) this exon is part of the 5' untranslated region (c.-58+1dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.61

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over