ENST00000345843.8:c.-47+3A>C

Variant names:

• chr4-26319891-A-C
• rs1371194134
• ENST00000345843.8:c.-47+3A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000345843.8(RBPJ):​c.-47+3A>C variant causes a splice region, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBPJ ENST00000345843.8 splice_region, intron
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.148
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302078 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000345843.8. 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_001374400.1		c.-58+121A>C		intron	N/A	NP_001361329.1	Q06330-1
	RBPJ	NM_005349.4		c.-58+3A>C		splice_region intron	N/A	NP_005340.2
	RBPJ	NM_001374401.1		c.-166-42555A>C		intron	N/A	NP_001361330.1	Q06330-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000345843.8	TSL:1	c.-47+3A>C		splice_region intron	N/A	ENSP00000305815.6	Q06330-5
	RBPJ	ENST00000342295.6	TSL:5	c.-58+3A>C		splice_region intron	N/A	ENSP00000345206.1	Q06330-1
	RBPJ	ENST00000512671.6	TSL:2	c.-58+121A>C		intron	N/A	ENSP00000423644.2	Q06330-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238324 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000145 AC: 2 AN: 1375652 Hom.: 0 Cov.: 28 AF XY: 0.00000145 AC XY: 1 AN XY: 687644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000321 AC: 1 AN: 31190

American (AMR) AF: 0.0000229 AC: 1 AN: 43716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 37694

South Asian (SAS) AF: 0.00 AC: 0 AN: 84404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1037696

Other (OTH) AF: 0.00 AC: 0 AN: 57184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		0.15
PromoterAI		-0.069	Neutral
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.68		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1371194134; hg19: chr4-26321513;