4-26320779-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RBPJ
NM_005349.4 missense

Scores

4
14

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20554039).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBPJNM_015874.6 linkc.-250C>A upstream_gene_variant ENST00000355476.8 NP_056958.3 Q06330-7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBPJENST00000355476.8 linkc.-250C>A upstream_gene_variant 1 NM_015874.6 ENSP00000347659.4 Q06330-7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1402728
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
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.:
33
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
Dec 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
D
BayesDel_noAF
Benign
-0.14
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
.;T;T
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.023
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.44
T;T;.
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.56
T
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
D
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.

Other links and lift over

dbSNP: rs1484367037; hg19: chr4-26322401; API