rs874040

Variant names:

• chr4-26106575-G-C
• rs874040
• XM_047415656.1:c.-50+797G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_047415656.1(RBPJ):​c.-50+797G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 151,966 control chromosomes in the GnomAD database, including 6,746 homozygotes. 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: 𝑓 0.29 (6746 hom., cov: 32)
• Consequence: RBPJ XM_047415656.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 60 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), Ambry Genetics, G2P
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBPJ	XM_047415656.1	c.-50+797G>C		intron_variant	Intron 1 of 11		XP_047271612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43666 AN: 151848 Hom.: 6735 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.295

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.288 AC: 43703 AN: 151966 Hom.: 6746 Cov.: 32 AF XY: 0.281 AC XY: 20867 AN XY: 74276

African (AFR) AF: 0.346 AC: 14345 AN: 41406

American (AMR) AF: 0.249 AC: 3802 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 923 AN: 3464

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5176

South Asian (SAS) AF: 0.134 AC: 643 AN: 4810

European-Finnish (FIN) AF: 0.272 AC: 2872 AN: 10552

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20133 AN: 67968

Other (OTH) AF: 0.291 AC: 614 AN: 2110

Alfa AF: 0.286 Hom.: 3694

Bravo AF: 0.292

Asia WGS AF: 0.0790 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.27
DANN	Benign	0.49
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs874040; hg19: chr4-26108197;