Genetic Variant RBPJ:c.20+1248G>C (chr4-26322296-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015874.6(RBPJ):c.20+1248G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 152,212 control chromosomes in the GnomAD database, including 816 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.091 ( 816 hom., cov: 32)

Exomes 𝑓: 0.10 ( 0 hom. )

Consequence

RBPJ
NM_015874.6 intron

Scores

Splicing: ADA: 0.00002193

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.338

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Adams-Oliver syndrome 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Adams-Oliver syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RBPJ links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015874.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RBPJ	NM_015874.6	MANE Select	c.20+1248G>C	intron	N/A	NP_056958.3
RBPJ	NM_001374400.1		c.59+1481G>C	intron	N/A	NP_001361329.1	Q06330-1
RBPJ	NM_005349.4		c.59+1481G>C	intron	N/A	NP_005340.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RBPJ	ENST00000355476.8	TSL:1 MANE Select	c.20+1248G>C	intron	N/A	ENSP00000347659.4	Q06330-7
RBPJ	ENST00000361572.10	TSL:1	c.59+1481G>C	intron	N/A	ENSP00000354528.6	Q06330-1
RBPJ	ENST00000348160.9	TSL:1	c.-167+1248G>C	intron	N/A	ENSP00000339699.5	Q06330-6

Frequencies

GnomAD3 genomes

AF:

0.0911

AC:

13857

AN:

152084

Hom.:

814

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0954

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.0674

Gnomad ASJ

AF:

0.0381

Gnomad EAS

AF:

0.307

Gnomad SAS

AF:

0.0587

Gnomad FIN

AF:

0.0830

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0845

Gnomad OTH

AF:

0.0850

GnomAD4 exome

AF:

0.100

AC:

AN:

Hom.:

Cov.:

AF XY:

0.125

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0911

AC:

13862

AN:

152202

Hom.:

816

Cov.:

AF XY:

0.0922

AC XY:

6864

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0953

AC:

3960

AN:

41548

American (AMR)

AF:

0.0673

AC:

1029

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0381

AC:

132

AN:

3468

East Asian (EAS)

AF:

0.307

AC:

1589

AN:

5172

South Asian (SAS)

AF:

0.0592

AC:

285

AN:

4818

European-Finnish (FIN)

AF:

0.0830

AC:

878

AN:

10580

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0845

AC:

5749

AN:

68012

Other (OTH)

AF:

0.0855

AC:

181

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

640

1280

1920

2560

3200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0513

Hom.:

Bravo

AF:

0.0904

Asia WGS

AF:

0.156

AC:

542

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.1

(source)

DANN

Benign

0.49

PhyloP100

-0.34

PromoterAI

0.073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over