4-26362494-C-A

Variant names:

• chr4-26362494-C-A
• ENST00000342320.8:c.-118C>A

Variant summary

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

The NM_203284.3(RBPJ):​c.-118C>A variant causes a 5 prime UTR 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBPJ NM_203284.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• 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 (BayesDel_noAF=-0.2).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203284.3. 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.21-23859C>A		intron	N/A	NP_056958.3
	RBPJ	NM_001374401.1		c.-118C>A		5_prime_UTR	Exon 2 of 12	NP_001361330.1	Q06330-6
	RBPJ	NM_001374402.1		c.-118C>A		5_prime_UTR	Exon 2 of 12	NP_001361331.1	Q06330-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000342320.8	TSL:1	c.-118C>A		5_prime_UTR	Exon 1 of 11	ENSP00000340124.4	Q06330-6
	RBPJ	ENST00000348160.9	TSL:1	c.-118C>A		5_prime_UTR	Exon 2 of 12	ENSP00000339699.5	Q06330-6
	RBPJ	ENST00000355476.8	TSL:1 MANE Select	c.21-23859C>A		intron	N/A	ENSP00000347659.4	Q06330-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1360450 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 670498

African (AFR) AF: 0.00 AC: 0 AN: 29870

American (AMR) AF: 0.00 AC: 0 AN: 27578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21142

East Asian (EAS) AF: 0.00 AC: 0 AN: 37582

South Asian (SAS) AF: 0.00 AC: 0 AN: 68826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3936

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065634

Other (OTH) AF: 0.00 AC: 0 AN: 55724

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.94
PhyloP100		1.4
PromoterAI		-0.011	Neutral

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: chr4-26364116;