4-26320793-C-T

Position:

• chr4-26320793-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000361572.10(RBPJ):​c.37C>T​(p.Pro13Ser) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBPJ ENST00000361572.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.908

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]

ACMG classification

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=0.12189233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBPJ	NM_001374400.1	c.37C>T	p.Pro13Ser	missense_variant	2/12		NP_001361329.1
RBPJ	NM_005349.4	c.37C>T	p.Pro13Ser	missense_variant	2/12		NP_005340.2
RBPJ	NM_001379408.1	c.37C>T	p.Pro13Ser	missense_variant	2/11		NP_001366337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJ	ENST00000361572.10	c.37C>T	p.Pro13Ser	missense_variant	1/11	1		ENSP00000354528
RBPJ	ENST00000345843.8	c.-47+905C>T		intron_variant		1		ENSP00000305815
RBPJ	ENST00000342295.6	c.37C>T	p.Pro13Ser	missense_variant	2/12	5		ENSP00000345206

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RBPJ-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 13 of the RBPJ protein (p.Pro13Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.19	.;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.54	T;T;.
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	.;L;L
MutationTaster	Benign	1.0	D;N;N
PROVEAN	Benign	0.18	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0020	.;B;B
Vest4		0.13, 0.086
MutPred		0.34		Gain of phosphorylation at P13 (P = 0.0075);Gain of phosphorylation at P13 (P = 0.0075);Gain of phosphorylation at P13 (P = 0.0075);
MVP		0.56
MPC		1.1
ClinPred		0.18	T
GERP RS		2.0
Varity_R		0.034
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-26322415;