4-26386369-C-A

Variant names:

• chr4-26386369-C-A
• NM_015874.6:c.37C>A
• RBPJ p.Pro13Thr

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015874.6(RBPJ):​c.37C>A​(p.Pro13Thr) variant causes a missense change. 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. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBPJ NM_015874.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2300084).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	NM_015874.6	MANE Select	c.37C>A	p.Pro13Thr	missense	Exon 2 of 11	NP_056958.3
	RBPJ	NM_001374400.1		c.76C>A	p.Pro26Thr	missense	Exon 3 of 12	NP_001361329.1	Q06330-1
	RBPJ	NM_005349.4		c.76C>A	p.Pro26Thr	missense	Exon 3 of 12	NP_005340.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000355476.8	TSL:1 MANE Select	c.37C>A	p.Pro13Thr	missense	Exon 2 of 11	ENSP00000347659.4	Q06330-7
	RBPJ	ENST00000361572.10	TSL:1	c.76C>A	p.Pro26Thr	missense	Exon 2 of 11	ENSP00000354528.6	Q06330-1
	RBPJ	ENST00000342320.8	TSL:1	c.34C>A	p.Pro12Thr	missense	Exon 2 of 11	ENSP00000340124.4	Q06330-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449432 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 720828

African (AFR) AF: 0.00 AC: 0 AN: 32752

American (AMR) AF: 0.00 AC: 0 AN: 43514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 83662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4932

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106084

Other (OTH) AF: 0.00 AC: 0 AN: 59810

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.052
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.056
Sift	Benign	0.072	T
Sift4G	Benign	0.44	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.47
Mutation Taster		=84/16	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-26387991;