Variant 4-26320779-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005349.4(RBPJ):c.23C>A(p.Pro8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RBPJ
NM_005349.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RBPJ. . Gene score misZ 3.5749 (greater than the threshold 3.09). Trascript score misZ 3.5998 (greater than threshold 3.09). GenCC has associacion of gene with Adams-Oliver syndrome 3, Adams-Oliver syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.20554039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
RBPJ	NM_001374400.1 linkuse as main transcript	c.23C>A	p.Pro8His	missense_variant	2/12	NP_001361329.1
RBPJ	NM_005349.4 linkuse as main transcript	c.23C>A	p.Pro8His	missense_variant	2/12	NP_005340.2	Q06330-1
RBPJ	NM_001379408.1 linkuse as main transcript	c.23C>A	p.Pro8His	missense_variant	2/11	NP_001366337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
RBPJ	ENST00000361572.10 linkuse as main transcript	c.23C>A	p.Pro8His	missense_variant	1/11	1	ENSP00000354528.6	Q06330-1
RBPJ	ENST00000345843.8 linkuse as main transcript	c.-47+891C>A		intron_variant		1	ENSP00000305815.6	Q06330-5
RBPJ	ENST00000342295.6 linkuse as main transcript	c.23C>A	p.Pro8His	missense_variant	2/12	5	ENSP00000345206.1	Q06330-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1402728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692134

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2024

The c.23C>A (p.P8H) alteration is located in exon 2 (coding exon 1) of the RBPJ gene. This alteration results from a C to A substitution at nucleotide position 23, causing the proline (P) at amino acid position 8 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.023

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.44

T;T;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.3

.;L;L

PROVEAN

Benign

-0.44

N;N;N

REVEL

Benign

0.036

Sift

Benign

0.034

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.085

.;B;B

Vest4

0.30, 0.23

MutPred

0.31

Loss of glycosylation at P8 (P = 0.0671);Loss of glycosylation at P8 (P = 0.0671);Loss of glycosylation at P8 (P = 0.0671);

MVP

0.38

MPC

1.2

ClinPred

0.89

GERP RS

3.9

Varity_R

0.23

gMVP

0.26

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

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