4-26320790-C-G

Position:

chr4-26320790-C-G

Variant summary

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

The NM_005349.4(RBPJ):c.34C>G(p.Pro12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RBPJ
NM_005349.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.460

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=0.09298769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
RBPJ	NM_001374400.1 linkuse as main transcript	c.34C>G	p.Pro12Ala	missense_variant	2/12	NP_001361329.1
RBPJ	NM_005349.4 linkuse as main transcript	c.34C>G	p.Pro12Ala	missense_variant	2/12	NP_005340.2	Q06330-1
RBPJ	NM_001379408.1 linkuse as main transcript	c.34C>G	p.Pro12Ala	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.34C>G	p.Pro12Ala	missense_variant	1/11	1	ENSP00000354528.6	Q06330-1
RBPJ	ENST00000345843.8 linkuse as main transcript	c.-47+902C>G		intron_variant		1	ENSP00000305815.6	Q06330-5
RBPJ	ENST00000342295.6 linkuse as main transcript	c.34C>G	p.Pro12Ala	missense_variant	2/12	5	ENSP00000345206.1	Q06330-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000624

AC:

AN:

160216

Hom.:

AF XY:

0.00

AC XY:

AN XY:

84802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1403384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692482

show subpopulations

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:

9.25e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Feb 02, 2024

The RBPJ c.34C>G variant is predicted to result in the amino acid substitution p.Pro12Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) 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

AlphaMissense

Benign

0.056

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.20

.;T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.42

T;T;.

M_CAP

Benign

0.077

MetaRNN

Benign

0.093

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.90

.;L;L

PROVEAN

Benign

-0.42

N;N;N

REVEL

Benign

0.094

Sift

Benign

0.53

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.012

.;B;B

Vest4

0.20, 0.18

MutPred

0.17

Loss of loop (P = 0.0075);Loss of loop (P = 0.0075);Loss of loop (P = 0.0075);

MVP

0.52

MPC

1.0

ClinPred

0.075

GERP RS

3.0

Varity_R

0.056

gMVP

0.18

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